Podcasts about angiotensin ii

N Engl J Med 2001;345:1667-1675Background: Angiotensin II is a peptide hormone that is part of the renin–angiotensin–aldosterone system (RAAS). Angiotensin II is a potent vasoconstrictor and growth-stimulating hormone. Data suggested that it plays a role in ventricular remodeling and progression of heart failure. Although treatment with angiotensin-converting enzyme inhibitors (ACEi) reduce angiotensin II levels, physiologically active levels of angiotensin II may persist despite long-term therapy.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.The Valsartan Heart Failure Trial (Val-HeFT) sough to assess whether the angiotensin-receptor blocker valsartan, could reduce mortality and morbidity when added to optimal medical therapy in patients with systolic heart failure.Patients: Eligible patients had left ventricular ejection fraction less than 40% and left ventricular dilation, in addition to having clinical heart failure for at least 3 months with NYHA class II, III or IV symptoms. Patient also had to have been receiving a fixed-dose drug regimen for at least two weeks, that could include ACEi, diuretics, digoxin, and beta-blockers.There were many exclusion criteria. We mention some here: Postpartum cardiomyopathy, acute myocardial infarction within 3 months, coronary artery disease likely to require intervention, serum creatinine >2.5 mg/dL and life expectancy less than 5 years.Baseline characteristics: Patients were recruited from 302 centers in 16 countries. The trial randomized 5,010 patients – 2,511 randomized to receive valsartan and 2,499 to receive placebo.The average age of patients was 63 years and 80% were men. The average left ventricular ejection fraction was 27%. Cardiomyopathy was ischemic in 57% of the patients. The NYHA class was II in 62% of the patients, III in 36% of the patients and IV in 2%.Approximately 26% had diabetes and 12% had atrial fibrillation.At the time of enrollment, 86% were taking a diuretic, 67% were taking digoxin, 35% were taking beta-blockers, and 93% were taking ACEi.Procedures: The trial was double-blinded. The trial had an initial run-in period for 2 - 4 weeks where patients received placebo twice daily. This was performed to confirm patients' eligibility, clinical stability and compliance.Patients were assigned in a 1:1 ratio to receive valsartan or placebo. Randomization was stratified according to whether or not they were receiving a beta-blocker.Valsartan was started at a dose of 40 mg twice a day, and the dose was doubled every two weeks to the target dose of 160 mg twice a day. Placebo doses were adjusted in a similar way.Follow up occurred at 2, 4, and 6 months and every 3 months thereafter.Endpoints: The trial had two primary end points. The first was all-cause mortality. The second was the combined end point of mortality and morbidity, which was defined as cardiac arrest with resuscitation, hospitalization for heart failure, or administration of intravenous inotropic or vasodilator drugs for four hours or more without hospitalization.The estimated sample size was 5,000 patients. The sample size calculation assumed 20% relative risk reduction in mortality with valsartan assuming 906 patients would die during the trial. This sample size would provide the trial 90% power at 0.02 alpha. Alpha was 0.02 instead of the traditional 0.05 since the trial had two primary endpoints and to adjust for the interim analyses.Results: The target valsartan dose of 160 mg twice a day was achieved in 84% of the patients. The reduction in systolic blood pressure was greater with valsartan vs placebo – mean of 5.2 ± 15.8 mm with valsartan compared to 1.2 ± 14.8 mm Hg with placebo, at 4 months.All-cause mortality was not different between both groups (19.7% with valsartan vs 19.4% with placebo, RR: 1.02, 95% CI: 0.88 – 1.18; p= 0.80). The second co-primary endpoint was reduced with valsartan (28.8% vs 32.1%, RR: 0.87, 95% CI: 0.77 – 0.97; p= 0.009). This was driven by reduction in hospitalizations for heart failure (13.8% vs 18.2%). Cardiac arrest with resuscitation was 0.6% with valsartan and 1.0% with placebo. All-cause hospitalization was numerically lower with valsartan, however, this was not statistically significance (2,856 vs 3,106; p= 0.14). The mean change in ejection fraction was higher with valsartan (4.0% vs 3.2%; p= 0.001). More patients had improvement in NYHA classification with valsartan (23.1% vs 20.7%; p

We sincerely apologize! During the livestream recording, we experienced some technical difficulties between 07:15 to 08:50. Thanks for your patience and understanding.Learn more about becoming an Insider on our website: https://www.benbikman.comDuring The Metabolic Classroom lecture this week, Dr. Bikman dives into the intricate relationship between salt- and water-regulating hormones and metabolic health.Starting with a discussion of the renin-angiotensin-aldosterone system (RAAS), he explains how hormones like angiotensin II, aldosterone, and antidiuretic hormone (ADH) are not only critical for regulating blood pressure but also significantly impact insulin sensitivity and fat cell dynamics. Angiotensin II promotes insulin resistance by increasing ceramide production, which blocks insulin signaling, while also enlarging fat cells and inhibiting their breakdown. Similarly, aldosterone exacerbates insulin resistance by enhancing ceramide levels and promotes both the growth and multiplication of fat cells. ADH complements these effects, particularly by inhibiting fat breakdown through its action on specific receptors.Ben emphasizes the counterintuitive finding that salt restriction, often prescribed to manage hypertension, can worsen insulin resistance, particularly in individuals with metabolic vulnerabilities. Studies highlight that reducing salt intake leads to increased fasting insulin levels, impaired glucose metabolism, and unfavorable lipid changes, such as reduced HDL cholesterol. Additionally, he warns that dehydration, much like salt restriction, activates these same hormonal pathways, compounding their metabolic effects.Dr. Bikman concludes with a reminder that interventions aimed at improving blood pressure should consider their broader metabolic implications, particularly for individuals predisposed to insulin resistance.Show Notes/References:For complete show notes and references referred to in this episode, we invite you to become a Ben Bikman Insider subscriber. As a subscriber, you'll enjoy real-time, livestream Metabolic Classroom access which includes live Q&A with Ben, ad-free Metabolic Classroom Podcast episodes, show notes and references, Ben's Research Reviews Podcast, and a searchable archive that includes all Metabolic Classroom episodes and Research Reviews. Learn more about becoming an Insider on our website: https://www.benbikman.comTimestamps: (approximate)(01:13) Overview of Salt- and Water-Regulating Hormones(02:22) How Angiotensin II Influences Blood Pressure and Insulin Resistance(06:37) The Metabolic Effects of Angiotensin II on Fat Cells(11:22) Aldosterone's Role in Insulin Resistance and Fat Cell Growth(15:57) Metabolic Impacts of Antidiuretic Hormone (ADH)(29:02) The Counterintuitive Effects of Salt Restriction on Metabolic Health(33:13) The Role of Dehydration in Activating Metabolic Hormones(34:51) Conclusion: How Blood Pressure Hormones Influence Metabolic Health#MetabolicHealth #InsulinResistance #Hypertension #SaltAndHealth #BloodPressure #HormonesAndHealth #DrBenBikman #MetabolicSyndrome #LowCarbLife #Type2Diabetes #KetoLife #HealthyLifestyle #NutritionScience #MetabolismMatters #HealthEducation #FatCellBiology #InsulinSensitivity #SaltIntake #Dehydration #HealthTips Hosted on Acast. See acast.com/privacy for more information.

Trial of the Week: ATHOS-3 Angiotensin II for the Treatment of Vasodilatory Shock Special Guest: Dr. Ashish Khanna, MD, MS, FCCP, FCCM, FASA Dr. Ashish Khanna joins me to highlight the ATHOS-3 trial, where Dr. Khanna is the principal investigator and first author of the NEJM publication. We discuss the history of angiogensin II, research prior to ATHOS-3, highlight findings from the ATHOS-3 trial, writing for NEJM, experience leading a large prospective RCT in the critically ill, what research do we have since this landmark publication, and much more. Reference list: https://pharmacytodose.files.wordpress.com/2023/09/athos3-references.pdf PharmacyToDose.Com  @PharmacyToDose  PharmacyToDose@Gmail.com Learn more about your ad choices. Visit megaphone.fm/adchoices

This week, I discuss which patients respond best to ATII and when to start it (hint: it's earlier than you think)Follow HERE! References:All references for Episode 91 are found on my Read by QxMD collectionSupport the showFind ER-Rx: - On Instagram: @ERRxPodcast - On the website: errxpodcast.com - On YouTube Disclaimer: The information contained within the ER-Rx podcast episodes, errxpodcast.com, and the @errxpodcast Instagram page is for informational/ educational purposes only, is not meant to replace professional medical judgement, and does not constitute a provider-patient relationship between you and the authors. Information contained herein may be accidentally inaccurate, incomplete, or outdated, and users are to use caution, seek medical advice from a licensed physician, and consult available resources prior to any medical decision making. The contributors of the ER-Rx podcast are not affiliated with, nor do they speak on behalf of, any medical institutions, educational facilities, or other healthcare programs.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.20.533428v1?rss=1 Authors: Xu, T., Chen, Z., Zhou, X., Wang, L., Zhou, F., Yao, D., Zhou, B., Becker, B. Abstract: The brain renin angiotensin II system plays a pivotal role in cognition and neuropathology via the central angiotensin II type 1 receptor (AT1R), yet the lack of a biologically informed framework currently impedes translational and therapeutic progress. We combined imaging transcriptomic and meta-analyses with pharmaco-resting state fMRI employing a selective AT1R antagonist in a discovery-replication design (n=132 individuals). The AT1R was densely expressed in subcortical systems engaged in reward, motivation, stress, and memory. Pharmacological target engagement suppressed spontaneous neural activity in subcortical systems with high AT1R expression and enhanced functional network integration in cortico-basal ganglia-thalamo-cortical circuits. AT1R-regulation on functional network integration was further mediated by dopaminergic, opioid and corticotrophin-releasing hormone pathways. Overall, this work provides the first comprehensive characterization of the architecture and function of the brain renin angiotensin II system indicating that the central AT1R mediates human cognition and behavior via regulating specific circuits and interacting with classical transmitter systems. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

This month on Episode 44 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the January 6th and January 20th issue of Circulation Research. This episode also features an interview with Dr Timothy McKinsey and Dr Marcello Rubino about their study, Inhibition of Eicosanoid Degradation Mitigates Fibrosis of the Heart.   Article highlights:   Prasad, et al. ACE2 in Gut Integrity and Diabetic Retinopathy   Cui, et al. Epsins Regulate Lipid Metabolism and Transport   Li, et al. Endothelial H2S modulates EndoMT in HF   Luo, et al. F. plautii Attenuates Arterial Stiffness   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'm going to be highlighting articles from our January 6th and January 20th issues of Circulation Research. I'm also going to have a chat with Dr Timothy McKinsey and Dr Marcello Rubino about their study, Inhibition of Eicosanoid Degradation Mitigates Fibrosis of the Heart. But before the interview, I want to get to a few articles to highlight.   Cindy St. Hilaire:        The first article is titled, Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes. The first authors are Ram Prasad and Jason Floyd, and the corresponding author is Maria Grant, and they are from the University of Alabama.   Type 1 Diabetes has a complex etiology and pathology that are not entirely understood. In addition to the destruction of insulin-producing cells, a recently discovered feature of the disease in both humans and in rodent models is that the levels of angiotensin converting enzyme 2 or ACE2 can be unusually low in certain tissues. ACE2 is a component of the renin angiotensin system controlling hemodynamics and interestingly, genetic deficiency of ACE2 in rodents exacerbates aspects of diabetes such as gut permeability, systemic inflammation and diabetic retinopathy, while boosting ACE2 has been shown to ameliorate diabetic retinopathy in mice. This study shows that ACE2 treatment also improves gut integrity and systemic inflammation as well as retinopathy. Six months after the onset of diabetes in a mouse model, oral doses of a bacteria engineered to express humanized ACE2 led to a reversal of the animal's gut barrier dysfunction and its retinopathy. Humans with diabetic retinopathy also displayed evidence of increased gut permeability in low levels of ACE2. This study suggests they may benefit from a similar probiotic treatment.   Cindy St. Hilaire:        The next article I want to highlight is titled, Epsin Nanotherapy Regulates Cholesterol Transport to Fortify Atheroma Regression. The first authors are Kui Cui, Xinlei Gao and Beibei Wang, and the corresponding authors are Hong Chen and Kaifu Chen and they're from Boston Children's Hospital. Epsins are a family of plasma membrane proteins that drive endocytosis. They're expressed at varying levels throughout the tissues of the body, and recent research shows that they are unusually abundant on macrophages within atherosclerotic lesions. In mice, macrophage specific Epsin loss results in a reduction in foam cell formation and atherosclerotic plaque development. This study now shows that this effect on foam cells is because Epsins normally promote the internalization of lipids into macrophages through their endosytic activity.   But that's not all. The proteins also impede cholesterol efflux from macrophages to further exacerbate lipid retention. It turns out out Epsins regulate the endocytosis and the degradation of a cholesterol efflux factor called ABCG1. Importantly, these pro atrogenic activities of Epsins can be stopped. Using macrophage targeted nanoparticles carrying Epson specific silencing RNA, the team could suppress reduction of the protein in cultured macrophages and could reduce the size and number of plaques in atherosclerosis prone mice. Together these results suggest blocking Epsins via nanotherapy or other means could be a therapeutic approach to stopping or slowing atherosclerotic plaque progression.   Cindy St. Hilaire:        The third article I want to highlight is coming from our January 20th issue of Circ Res and is titled, Hydrogen Sulfide Modulates Endothelial-Mesenchymal Transition in Heart Failure. The first author is Zhen Li, and the corresponding author is David Lefer and they're from Cedars-Sinai. Hydrogen sulfide is a critical endogenous signaling molecule that exerts protective effects in the setting of heart failure. Cystathionine γ-lyase, or CSE, is one of the three hydrogen sulfide producing enzymes, and it's predominantly localized in the vascular endothelium. Genetic deletion of CSE, specifically in the endothelium, leads to reduced nitric oxide bioavailability, impaired vascular relaxation and impaired exercise capacity, while genetic over-expression of PSE in endothelial cells improves endothelial cell dysfunction, and attenuates myocardial infarction following myocardial ischemia-reperfusion injury.   In this study, endothelial cell specific CSE knockout mice and endothelial cell specific CSE overexpressing transgenic mice were subjected to transverse aortic constriction to induce heart failure with reduced ejection fraction. And the goal was to investigate the contribution of the CSE hydrogen sulfide access in heart failure. Endothelial specific CSE knockout mice exhibited increased endothelial to mesenchymal transition and reduced nitric oxide bioavailability in the myocardium. And this was associated with increased cardiac fibrosis, impaired cardiac and vascular function, and it worsened the vascular performance of these animals. In contrast, genetic overexpression of CSE in endothelial cells led to increased myocardial nitric oxide, decreased EndoMT and decreased cardiac fibrosis. It also improved exercise capacity. These data demonstrate that endothelial CSE modulates endothelial mesenchymal transition and ameliorated the severity of pressure overload induced heart failure , in part through nitric oxide related mechanisms. This data further suggests that endothelium derived hydrogen sulfide is a potential therapeutic for the treatment of heart failure with reduced ejection fraction.   Cindy St. Hilaire         The last article I want to highlight is titled, Flavonifractor plautii Protects Against Elevated Arterial Stiffness. The first authors are Shiyun Luo and Yawen Zhao, and the corresponding author is Min Xia, and they are at Sun Yat-sen University. Dysbiosis of gut microbiota contributes to vascular dysfunction and gut microbial diversity has been reported to be inversely correlated with arterial stiffness. However, the causal role of gut microbiota in the progression of arterial stiffness and the specific species along with the molecular mechanisms underlying this change remain largely unknown. In this study, the microbial composition in metabolic capacities were compared in participants with elevated arterial stiffness and in normal controls free of medication. And these groups were age and sex match.   Human fecal metagenomic sequencing identified a significant presence of Flavonifractor plautii or F. plautii in normal controls, which was absent in the subjects with elevated arterial stiffness. The microbiome of normal controls exhibited an enhanced capacity for glycolysis and polysaccharide degradation, whereas individuals with increased arterial stiffness exhibited increased biosynthesis of fatty acids and aromatic amino acids. Additionally, experiments in the angiotensin II induced and humanized mouse model show that replenishment with F. plautii or its main effector cis-aconitic acid or CCA improved elastic fiber network and reversed increased pulse wave velocity through the suppression of matrix metalloproteinase-2 and through the inhibition of monocyte chemoattractant protein-1. And this was seen in both the angiotensin II induced and humanized models of arterial stiffness. This study now identifies a novel link between F. plautii and arterial function and raises the possibility of sustaining vascular health by targeting the gut microbiota.   Cindy St. Hilaire:        Today with me I have Dr Tim McKinsey and Dr Marcello Rubino from the University of Colorado Anschutz Medical Campus, and we're here to talk about their paper Inhibition of Eicosanoid Degradati`on Mitigates Fibrosis of the Heart. And this article is in our January 6th issue of Circulation Research, so thank you both so much for joining me today.   Timothy McKinsey:    Thank you for inviting us.   Marcello Rubino:        Yeah, thank you for the opportunity.   Cindy St. Hilaire:        And so Dr McKinsey, you're a professor at the University of Colorado. How long have you been investigating cardiac fibrosis?   Timothy McKinsey:    Oh, a long time. Before I started the lab here in 2010, I was in industry working in biotech with Myogenic Gilead, and we were very interested in cardiac fibrosis all the way back then.   Cindy St. Hilaire:        Oh wow, so you actually made an industry to academia transfer.   Timothy McKinsey:    Yes.   Cindy St. Hilaire:        Good topic for another podcast. That is really great.   Timothy McKinsey:    Yeah, it's of interest to a lot of people, including trainees.   Cindy St. Hilaire:        Yeah, I bet. Dr Rubino, you were or are a postdoc in the McKinsey lab? Marcello Rubino:        Yeah, I was a postdoc in Timothy McKinsey lab. I spent four years in Tim's lab. It was my first time studying cardio fibrosis, so it was a little bit difficult at the end, but I think I was right choosing Tim, so I'm really happy now.   Cindy St. Hilaire:        Nice and are you sticking with fibrosis or are you moving on?   Marcello Rubino:        Yeah, so now I'm back in Milan where I did my PhD student and postdoc. I am like an independent researcher, but it's still not a principal investigator, so I want to become one of the that, studying cardiac fibrosis. Yeah. And inflammation and epigenetics, so yeah, I'm going try to go to my way, thanks to Tim, I think that I find my own way.   Cindy St. Hilaire:        I'm sure you will. I mean, based on the great work in this study, right. Building upon that, I'm sure you'll be a success.   Timothy McKinsey:    No doubt about it.   Cindy St. Hilaire:        So your manuscript, this study, it's investigating whether eicosanoid availability can attenuate fibrosis in the heart. But before we kind of jump into this study, why is fibrosis in the heart a bad thing? Is it always detrimental? Is there some level of fibrosis that's necessary or even helpful?   Timothy McKinsey:    I mean, a certain level of extracellular matrix is deposited in your heart and that maintains the structure of the heart. Fibrosis can also be good after you have a myocardial infarction and a big piece of the muscle of your heart has died, it needs to be replaced with a fibrotic scar, essentially to prevent rupture of the ventricle. So fibrosis isn't always bad, but chronic fibrosis can be really deleterious to the heart and contribute to stiffening of the heart and cause diastolic dysfunction. It can create substrates for arrhythmias and sudden cardiac death. So we're really trying to block the maladaptive fibrosis that occurs in response to chronic stress.   Cindy St. Hilaire:        Yeah, yeah. And what about eicosanoids? What are they and what role do they play in cardiac fibrosis or what was known about their role in this process before your study?   Timothy McKinsey:    Eicosanoids are lipids, they're basically fatty acids, 20 carbon in length and a lot is known about them. It's a very complex system. There are many different eicosanoids, but they're produced from arachidonic acid through the action of cyclooxygenase enzymes like COX-2. And so you're probably familiar with the literature showing that non-steroidal anti-inflammatory drugs that target the COX enzymes can actually increase the risk of cardiac disease, so there was a lot known about what produces eicosanoids in the heart, but our study is really the first to address how they're degraded and how that controls cardiac fibrosis.   Cindy St. Hilaire:        What I thought you did really well in the introduction and what I guess I didn't really fully appreciate until I had read your study, was that your goal was to identify compounds that could attenuate fibrosis. And you spent some time emphasizing the differences between a targeted small molecule screen and a phenotype based screen. And I was wondering if you could just expand on this difference for the audience and maybe just explain why in your case you went with the latter.   Timothy McKinsey:    Well, we wanted to use an unbiased approach and some people call this a chemical biology approach where we took a targeted library, meaning we took compounds with known activities, meaning compounds that with known targets and we screened that library using a phenotypic assays that we developed in the lab. And the phenotypic assay is an unbiased assay, right? We're just screening for compounds that have the ability to block the activation of fibroblasts. And we monitor activation by looking at markers of fibroblast activation such as alpha smooth muscle Actin. And we can do this in a very quantitative and high throughput manner using this imaging system, high content imaging system that we have in the lab.   It was an unbiased screen looking for inhibitors of fibroblasts activation across organ systems. We not only studied cardiac fibroblasts, but we also studied lung and renal fibroblasts looking for compounds with a common ability to block the activation state of each of those cell types.   One of the things that I get asked frequently is how do we maintain the cardiac fibroblasts in a quiescent state? Because you may know this, but when fibroblasts are plated on cell culture plastic, which has a very high 10 cell strength, they tend to spontaneously activate, so we actually spent a couple of years working out the conditions to maintain the cells in quiescent state, and I think that will also be of great interest to the field.   Cindy St. Hilaire:        Probably even the smooth muscle cell biology field where I hang out and even valve interstitial cells that we study. All of those, I guess basic things related to cell culture, we have taken for granted that plastic is not physiological.   Timothy McKinsey:    Right.   Cindy St. Hilaire:        And so I think with this really nice phenotypic or chemical screen that you conducted, you first identified nine compounds, but what made you zero in on this one, SW033291?   Timothy McKinsey:    When we got the hits, we were intrigued by the SW compound SW033291 because there was only one paper describing its action and there was a paper published in Science showing that SW or inhibition of this enzyme 15-PGDH could enhance organ regeneration.   Cindy St. Hilaire:        Oh, okay.   Timothy McKinsey:    And there's a very interesting interplay between fibrosis and organ regeneration where fibrosis inhibits regeneration and if you can stimulate regenerative pathways, they can actually block fibrosis, so there's this back and forth. And so that's really the main reason we were interested in pursuing SW just because of the novelty and the potential. And also it was a compound that behaved beautifully in our cell culture models with beautiful dose-dependent inhibition of each of the fibroblast types.   Cindy St. Hilaire:        It's kind of like the cleanest thing to start with. Also, if there's nothing known, it's ripe for investigation, so that's great. You just said this SW compound acts on 15-PGDH, so what is the role of that protein in fibroblasts and what if any known effects are there on this protein's inhibition in other cell types or disease states?   Marcello Rubino:        In fibroblasts team, I would like to say that this was really the first article that was published. Maybe there was just one published in Pulmonary Fibrosis, but like last year, but I didn't really talk about 15-PGDH, so you need to consider that 15-PGDH is an inhibitor, an enzyme that degrades prostaglandin, so if you inhibit the inhibitor, the release increase production, a lot of prostaglandin. And so a lot of paper were talking about this effect, so they will see we are just using SW in order to increase Prostaglandin E2 level and that was why we had this like anti-inflammatory or whatever effect. I would like to say that until now, maybe this can be the first really paper talking about no more than not just prostaglandin but 15-PGDH. Its action total level, a global level at particularly on fibroblasts.   To answer your question, I would like to say that this was also our question first and we checked by level other browser to try to find the answer to your question. We figured out that it was known that 15-PGDH was increasing a pathology condition in different organ, not just related by fibroblasts, not just related to cardiac disease, about the function with discover a function in macrophage that interested us because it can regulate maybe the polarization macrophage, so still involving the prostaglandin production inflammation, so that's why also we decide to take a look because it was still novel in fibrolbasts and we still know that it was doing something important and we were trying not to put the piece together and find something new in that we were lucky for this.   Timothy McKinsey:    15-PGDH is actually expressed at very low levels in fibroblasts. It's much more highly expressed in macrophage, just as Marcello pointed out, so in the future we're very interested in knocking out or inhibiting 15-PGDH in different cell types to see how that contributes to inhibition of cardiac fibrosis.   Cindy St. Hilaire:        Really interesting. Related to that, you used a couple different animal models for fibrosis. They're all different or special in their own way. How well did these recapitulate what we observe in humans. Are there any limitations of benefits?   Timothy McKinsey:    They're always limitations to animal models. We started out with a very robust commonly used model of cardiac fibrosis, which relies on Angiotensin II infusion in mice. We like that model because it's robust and quick so we can get answers quickly. And then we transitioned into a model of diastolic dysfunction that we've been working with in a lab where we remove a kidney from a mouse and we implant something called DOCA, which is an aldosterone memetic. And so the animals develop hypertension that leads to a mild but significant diastolic dysfunction with preserved ejection fraction.   And that's a model that we like a lot. It has something that we call hidden fibrosis, so if you just do standard histochemical staining of the hearts from the DOCA unit, nephrectomy model, that diastolic dysfunction model, you really can't see robust fibrosis. It's only when you dive more deeply with more sensitive assays like mass spectrometry or atomic force microscopy that you can detect this fibrosis and stiffening of the heart, so we usually lead with a robust model of fibrosis, cardiac fibrosis, and then transition into a slightly more complex model but more physiologically relevant model or disease relevant model.   Cindy St. Hilaire:        Obviously you showed some really nice robust results with this SW compound. So in the continuum of heart failure in human, what do you think or what would you speculate would be the ideal timeframe for administration of this compound?   Timothy McKinsey:    Wouldn't want to give it immediately after someone's had a heart attack. As we discussed earlier, you need that reparative scar to form so you don't want to block that fibrotic remodeling. We believe that there's kind of smoldering fibroblast activation in the heart, even in someone who's had heart disease for many, many years. And if we can dampen that, we can either prevent further progression of heart failure or perhaps reverse it. We don't really know if we can reverse really established fibrosis in the heart yet. But I would want to try to catch fibrosis fairly early on in the disease process in someone who has chronic hypertension or obesity or a variety of different comorbidities and then start delivering an antifibrotic therapy at that point.   Marcello Rubino:        I would like to add that, so it is really tricky when we talk about clinical trials because a lot of molecules that maybe they can work hopefully in a preclinical model don't work at the end in the clinical model. That's because can be some off target also like you just asked what is really important is when you do the administration of the molecule and talk about this in SW, like things say we don't want to prevent the fibrosis because there is something like called a kneeling at the beginning, so it is the good fibrosis we like to say, but the good thing of SW compound is that is affecting in a good way the proliferation of fibroblast that is different for all the other. I would like to say all the other inhibitor that we saw so far, because I remember the first time that I presented this work, there was an expert told me that he didn't believe that all my data because the compound was inhibiting fibrosis, it was inhibiting proliferation.   And I show him, no, this is contrary, so oh okay, I like it. We need to consider this that the action seems to be not like the retire for the cell, so because the cells continue to proliferate, they can proliferate more. But the good thing and we need to investigate more is that SW action seems to increase when the cell are more fibrotic, because we show just few human fibroblasts isolating from a human patient and we saw a higher positive effect of SW compound when the cell were more fibrotic. That can be interesting. I think that it's worth to try to test in the future like in different preclinical models and maybe in patients at the end because if we really can find something like maybe SW that can be specific for the state of pathology, that will be wonderful. I don't really know if we can really do it, but we need some therapy like this, so that's why we were really excited about what we discovered for this compound.   Timothy McKinsey:    We have a lot more to learn about this pathway and about fibrosis in general.   Cindy St. Hilaire:        Yeah.   Timothy McKinsey:    It's a very exciting time to be doing science because of the amazing technologies that we have at our disposal to address detailed mechanisms of disease.   Cindy St. Hilaire:        What was the most challenging aspect of the study?   Timothy McKinsey:    This was an incredibly difficult study. I can't even stress to you how much work went into this. Spearheaded by Marcello's awesome leadership. There was huge input from a big team. Keith Cook and I worked together in industry and we were able to recruit him over here for a few years as part of our fibrosis center called the CFReT. It's an advertisement. And Keith was able to implement some of the drug discovery approaches that we used in biotech and create this imaging system that we initially employed for the screens. That was challenging. Maintaining the cells in a quiescent state was very challenging as I mentioned. That took a couple of years and then just following up on SW and trying to figure out its mechanism of action was really challenging as well because as Marcello mentioned, most people have attributed SW's effects to an increase in PGE2 levels, so PGE2 is an eicosanoid that is degraded by 15-PGDH.   And definitely when you inhibit 15-PGDH with SW, you see increased PGE2. But surprisingly we couldn't find that PGE2 was doing anything in our cell culture systems, meaning when we added it exogenously it was not blocking fibroblast activation, so then Marcello set out to identify which eicosanoid that is regulated by 15-PGDH is actually the antifibrotic eicosanoid. And that led him to something called 12(S)-HETE. That was challenging. And then just determining at the molecular level what was going on was also challenging. And that led Marcello to this kind of paradoxical discovery that it activating ERK signaling was actually blocking fibroblast activation.   Cindy St. Hilaire:        And of course ERK does everything right?   Marcello Rubino:        It does. Everything.   Timothy McKinsey:    And sort of the dogma is that ERK is promoting fibrosis in the heart, but Marcello's data suggests otherwise.   Timothy McKinsey:    And then other shout outs, Josh Travers, who's the second author of the paper provided huge input, especially after Marcello left. Josh helped get this across the finish line. We have an amazing in vivo team conducting the animal model studies. Maria Cavasin and Elizabeth Hardy. I could go on and on. There are a lot of authors and if I didn't mention one of them, it doesn't mean that they weren't key contributors. I just wanted to throw that out there. We also had great collaborators. I think another component of this paper that is of great interest to us, and initially I was against doing any of this, is that Marcello and Josh created this biobank of human cardiac fibroblasts that we obtained from explanted hearts from individuals undergoing heart transplantation.   And initially I thought it was going to be a waste of time and money for Marcello and Josh to do that, but they were persistent and they started isolating these cells. And the cells are really fascinating because even after you take them out of that failed human heart and culture them, they maintain this constituently active state, which is different than the cells we were using for screening where we kept them quiescent and then we stimulated them with TGF-β to activate them. These human cardiac fibroblasts from the failed human hearts are just on all the time.   Cindy St. Hilaire:        Wow.   Timothy McKinsey:    And SW does a really amazing job of reversing that activated state.   Cindy St. Hilaire:        Very cool and excellent resource I'm sure for future studies. So my last question is what's next? You know, you discovered a lot in this paper. What's the next thing you want to tackle?   Timothy McKinsey:    Cell type specific roles for 15-PGDH in the heart, in the control of cardiac homeostasis and disease. Basically we want to knock it out in fibroblasts. We want to knock it out in our macrophages and see what the consequences are. That's one thing. We want to really pursue the whole GPR31 12(S)-HETE pathway in the heart. That's something that has never been studied. And so GPR31 is a G protein coupled receptor that is bound by this eicosanoid called 12(S)-HETE. And that seems to be blocking fibroblast activation, so we're going to further pursue that pathway. And then we think that this paradoxical finding related to ERK signaling in the heart is also worthy of pursuit. Why is it that stimulating ERK in a cardiac fibroblast is actually blocking the activation state of that cell?   Marcello Rubino:        I'm interested in this like Tim says, but also interested in the role of the interaction of the cell because it's important to study like a specific gene inhibitor, whatever role in a specific cell, but what happened to the other cell, the interaction the other cell when you do knocking in some specific cell, so that's what I'm trying to do in general. Now I move back in Italy, like I told you, I'm like a kind of independent research and I'm studying a lot single cell sequencing right now. Try to do also try to see what happened to interaction, understand during pathology.   The idea is to study like inhibitor treatment and to see what really happened because gene expression is important, but we need to consider also of course the protein shape, the protein interaction, the cell interaction, so I try to grow in this field and see what really happened because the problem of the cell, they're just cell in vitro. They can mimic what happened, but it's not what really happened in vivo, so can we use this novel technology to improve our knowledge, that's what I want to try to do.   Cindy St. Hilaire:        Well that's great. Dr McKinsey, Dr Rubino, thank you so much for taking the time to speak with me today. Title of their article was Inhibition of Eicosanoid Degradation Mitigates Fibrosis of the Heart. It's in our January 6th issue of Circ Res. And thank you both so much for joining me today and thank you to you and all of your colleagues who worked so hard on this for this amazing study.   Timothy McKinsey:    Thank you. We really enjoyed this visit and we're grateful to have our work published in Circulation Research.   Cindy St. Hilaire:        That's it for highlights from the January 6th and 20th 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 guests, Dr Tim McKinsey and Dr Marcello Rubino. This podcast is produced by Ishara Rantayaka, edited by Melissa Stoner and supported by the editorial team of Circulation Research. Some of the copy text 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 in basic cardiovascular research. This program is copyright of the American Heart Association 2022. The opinions expressed by the speakers of this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, please visit ahajournals.org.  

Vasoactives in Septic Shock Part II Special Guest: Patrick M. Wieruszewski, Pharm.D., BCCCP   Reference List: https://pharmacytodose.files.wordpress.com/2021/12/vasoactives-in-septic-shock-ii-references.pdf   02:51 – Background into vasodilatory shock and its outcomes; 04:14 – Signs/symptoms of septic shock; 05:09 – Norepinephrine as first-line vasopressor; 09:05 – Using second-line vasopressors; 17:04 – Human physiology and hemodynamics; 21:02 – More important: time to treatment or vasopressor choice; 22:16 – Taking biomarkers/genetic markers from the research lab to clinical practice; 28:22 – Vasopressin use in septic shock; 43:14 – Angiotensin II updates; 66:00 – Epinephrine in septic shock; 69:32 – Vasopressor stewardship; 72:40 – One wish for septic shock management   PharmacyToDose.Com @PharmacyToDose on Twitter PharmacyToDose@Gmail.com

On this ID the Future, physician Howard Glicksman and host Eric Anderson dive deeper into the body's exquisite blood pressure control system, cueing off a new discovery described at Science Daily as uncovering “the location of natural blood-pressure barometers inside our bodies that have eluded scientists for more than 60 years.” According to the primary research paper at Circulation Research, “Renin-expressing cells are essential for survival, perfected throughout evolution to maintain blood pressure (BP) and fluid-electrolyte homeostasis.” How did evolution perfect the system? How did it originate the system? The paper never says. The mention of evolution appears to be little more than a de rigueur genuflection before the reigning paradigm of blind evolution. What is bearing actual fruit, according to Glicksman Read More › Source

CoQ10 supplementation associated with improved trauma patient outcomes Urmia University of Medical Sciences (Iran) July 23 2021.    Findings from a trial reported on July 12, 2021 in the Journal of Nutritional Science revealed benefits for hospitalized traumapatients who were given supplements that contained coenzyme Q10.  The trial enrolled 40 men and women with traumatic injury and low plasma levels of CoQ10. Participants received a placebo or 400 milligrams CoQ10 daily for seven days. Blood samples collected at the beginning and end of the trial were analyzed for interleukin 6 (IL-6), which may be elevated during inflammation, and the oxidative stress markers malondialdehyde (MDA) and thiobarbituric acid reactive substances (TBARS). Body composition was also assessed at these time points, as well secondary outcomes that included Sequential Organ Failure Assessment (SOFA) and the Glasgow Coma Scale (GCS).  While interleukin-6 levels at the beginning of the study were similar between the CoQ10 and placebo groups at an average of 175.05 pg/mL and 177.82 pg/mL, they were reduced by 76.99 pg/mL in the CoQ10 group and 17.35 pg/mL in the placebo group. MDA values averaged 232.37 picograms per milliliter (pg/mL) and 239.96 pg/mL and were lowered by 88.84 pg/ml among participants who received CoQ10 and by 26.23 pg/mL among those who received a placebo. In comparison with the placebo group, fat free mass, skeletal muscle mass and body cell mass increased among those who received CoQ10. GCS and SOFA scores, and duration of hospital stay, ICU stay and ventilator use also improved among treated patients.  “To date, no randomized clinical trial study has been conducted to evaluate the effect of CoQ10 supplementation in traumatic mechanical ventilated patients and we hypothesized that CoQ10 administration in these patients could have beneficial effects on biochemical and clinical factors,” the authors wrote. “We have shown that CoQ10 could improve some of the clinical and anthropometric parameters in patients with a traumatic injury.”     Nigella sativa (black seed) prevents covid-induced vascular damage, scientists conclude   Oriental Institute of Science and Technology (India), July 27, 2021 New research published in the journal Vascular Pharmacology shows that Nigella sativa, also known as black seed or black cumin, binds to ACE2 in the lungs, effectively stopping the Wuhan coronavirus (Covid-19) from inducing inflammation and vascular damage. Researchers out of India investigated the effects of nigellidine, an indazole alkaloid of black seed, using molecular docking for binding to different angiotensin-binding proteins, as well as the Chinese Virus spike glycoprotein. They found that nigellidine “strongly binds” to the Chinese Virus spike protein at what is known as the hinge region or active site opening, which may in turn hamper its binding to the nCoV2-ACE2 surface. “Nigellidine effectively binds in the Angiotensin-II binding site / entry pocket,” the study explains. “Nigellidine showed strong binding to mono / multi-meric ACE1.” This process of ACE blocking could, the study goes on to suggest, restore angiotensin levels and restrict vasoturbulence in Chinese Virus patients, while the receptor blocking could help to stop resulting inflammation and vascular impairment. “Nigellidine may slow down the vaso-fluctuations due to Angiotensin deregulations in Covid patients,” the paper further explains. “Angiotensin II-ACE2 binding (ACE-value -294.81) is more favorable than nigellidine-ACE2. Conversely, nigellidine-ACE1 binding-energy / Ki is lower than nigellidine-ACE2 values indicating a balanced-state between constriction-dilatation.” Nigellidine also binds to the viral spike proteins, which when taken by Chinese Virus patients, and especially those who fall in the elderly category, could greatly reduce their risk of suffering complications or death. Nigellidine impairs SARS-CoV-2 infection, “cytokine storm” through numerous mechanisms In a related study that was published last year in the journal Europe PMC, researchers learned that nigellidine inhibits the Chinese Virus infection in several other ways. It was discovered early on in the “pandemic” that many of those who tested “positive” for the virus were suffering associated “cytokine storms,” in which their immune systems were over-responding and causing more damage, or even death. Nigellidine was then studied and discovered to possess certain properties that inhibit cytokine storms, as well as impede the SARS CoV-2 virus from causing infection. It is also hepato- and reno-protective, meaning it protects against liver damage. Beyond this, nigellidine was determined to possess unique immunomodulatory and anti-inflammatory characteristics, as well as antioxidant potential strong enough to inhibit important proteins associated with the Chinese Virus. In their quest to uncover possible “drug” candidates to protect patients against hyper-inflammation and other associated problems, the researchers learned that nigellidine – and more than likely other black seed constituents – helps tremendously with preventing negative side effects. Along with nigellicine, nigellidine is found in the seed coat of Nigella sativa. Both of these constituents in their sulfated forms are extremely bioavailable, and along with thymoquinone and dithymoquinone, two other black seed components, they show strong antioxidant, antibacterial, anti-hypertensive, anti-inflammatory and immunomodulatory effects. Black seed extracts have been shown in other experiments to decrease oxidative stress, effectively lowering the risk of inflammation-related diseases. We now know that this includes the Wuhan coronavirus (Covid-19). Black seed is also recognized as a metabolic protector, helping to improve lipid and blood sugar levels. “Most importantly, in SARS CoV-2 infection ACE-2 mediated impairment of aldosterone system may be repaired by,” the study further explains, providing relevant information to the current “pandemic.” “Vasorelaxant and anti-hypertensive function of [black seed] helps in the modulation of renin angiotensin system (RAS) or the diuretic activity, which is one of the major targets of COVID. It might have great protective role during post infective secondary disorder of the peripheral vasculature namely cardiac and renal systems. In most of the instances patients die due to this organ dysfunction/failure in COVID-19 infection.” By quelling inflammation, black seed could save lives from covid Laboratory studies have found that intake of Nigella sativa significantly improves the parameters for hyperglycemia and diabetes control, as well as glycated hemoglobin and insulin resistance. Based on this, experts believe that nigellidine specifically could play an important role in fighting the Chinese Virus by “docking” to the proteins and inflammatory molecules that can cause a cytokine storm – mainly TNF-? receptors such as TNFR1, TNFR2 and IL1R. “In the experimental rat model the source of this drug Nigella sativa; black cumin seed extracts were tested for its role on antioxidant, hepatic and renal status,” the paper states. “This work will help in the urgent therapeutic intervention against COVID-19 global pandemic.” “In the current study, we have decisively shown by molecular modeling that nigellidine can bind in the active sites of several important proteins of SARS CoV 2, several host receptors specific for SARS CoV-2 induced inflammatory markers IL1, IL6, TNF-?. Moreover, the extract from black cumin seed has been shown in experimental rat to be highly antioxidative, hepato- and reno-protective. Further studies are necessary to verify the potential effects of nigellidine in in vivo laboratory experimental animal model.”   Vitamin D supplementation improves recovery time of children with pneumonia at pediatric hospital Cairo University (Egypt), July 20, 2021 According to news reporting originating from Cairo, Egypt, by NewsRx correspondents, research stated, “Despite the well-recognized effect of vitamin D in metabolism and homeostasis, there is now growing interest in its probable association with pneumonia. This study aims to supply vitamin D3 (Cholecalciferol) (100,000 IU) to pneumonic children to minimize the duration of illness and improve their outcome.” Our news editors obtained a quote from the research from Cairo University, “A double-blinded, randomized, placebo-controlled trial was conducted in a Pediatric Cairo University affiliated hospital. An intervention arm (93 children) and a control arm (98 children), who had pneumonia with an insufficient or deficient level of vitamin D and whose parental permission was obtained, were enrolled in the trial. All children were treated with antibiotics according to WHO guidelines. Children were given a single injection of 1 mL of 100,000 IU of vitamin D3 or placebo. Clinical data were recorded every eight hours for all children. Outcomes were assessed 7 days after vitamin D injection. The primary outcome variable was the change in serum level of 25(OH)D, while the secondary outcomes were the medical state of the assigned cases (improvement or death) and duration between enrollment and hospital discharge for improved cases. In the supplementation group, the percentage of patients who suffered either deficient (38.7%) or insufficient levels (61.3%) of 25 (OH)D at day one had significantly decreased in the seventh day to (11.8%) and (52.7%), respectively. Kaplan--Meier plots highlighted that the median time to recover of the placebo group was significantly longer than that of the supplementation group (Log Rank P value < .001). VDD was detected in pediatric critical care children.” According to the news editors, the research concluded: “In pneumonic children with high VDD, it is illustrated that Vitamin D supplementation is accompanied by lowered mortality risk and pSOFA scores, reduced time to recover, and improved PaO2/FiO(2).”   Physical activity could combat fatigue, cognitive decline in cancer survivors University of Illinois, July 26, 2021 A new study indicates that cancer patients and survivors have a ready weapon against fatigue and "chemo brain": a brisk walk. Researchers at the University of Illinois, along with collaborators at Digital Artefacts in Iowa City, Iowa, and Northeastern University in Boston, looked at the association between physical activity, fatigue and performance on cognitive tasks in nearly 300 breast cancer survivors. "The data suggest that being more physically active could reduce two of the more commonly reported symptoms in breast cancer survivors: fatigue and cognitive impairment," said study leader Edward McAuley, a professor of kinesiology and community health at Illinois. "Most people think, 'If I exercise, I'll become tired.' In our study, exercise actually was associated with reduced fatigue, which in turn was associated with better cognitive function." Cognitive impairment, such as memory problems or shortened attention spans, is a common complaint among cancer patients and survivors, and is thought to be similar to decline due to aging. Past Illinois research has explored the effect of physical fitness on age-related cognitive decline, so the researchers wondered whether cancer survivors would respond similarly to exercise. "Other studies of cancer survivors have relied on small samples of cancer survivors, and used self-reporting measures of physical activity and cognitive function, which can be very biased," said postdoctoral researcher Diane Ehlers, the first author of the study, which is published in the journal Breast Cancer Research and Treatment. "What makes our study novel is that we had objective measures for both physical activity and cognitive performance, and a nationwide sample of breast cancer survivors." The researchers worked with Digital Artefacts -- developer of the commercial neuroscience app BrainBaseline - to create an iPad app tailored to this study. The app included questionnaires and activities designed to measure attention, memory and multitasking skills. The researchers also sent each participant an accelerometer to track daily physical activity. "We found that higher levels of daily moderate-to-vigorous physical activity were associated with better performance on the cognitive tasks measuring attention, memory and multitasking," Ehlers said. "What was notable was that physical activity's effect on cognitive performance was mediated by fatigue. This provides evidence that physical activity interventions targeting fatigue in cancer patients and survivors might provide promising models for improving cognitive function as well." Next, the researchers plan to conduct further studies to establish causation and further explore the pathways of how physical exercise improves cognitive performance. They are working with Digital Artefacts to conduct an iPhone-based study and focusing on diverse populations of breast cancer survivors. "The message for cancer patients and survivors is, get active!" Ehlers said. "Even if it's 10-minute bouts of brisk walking. It's not a magical cure-all, but we've seen many benefits of physical activity for cancer patients and survivors."   Cannabidiol promotes oral ulcer healing by inactivating CMPK2-mediated NLRP3 inflammasome Sichuan University (China), July 26, 2021 Xingying Qi, West China Hospital of Stomatology, Sichuan University, Chengdu, China, presented the oral session "Cannabidiol Promotes Oral Ulcer Healing by Inactivating CMPK2-Mediated NLRP3 Inflammasome" at the virtual 99th General Session & Exhibition of the International Association for Dental Research (IADR), held in conjunction with the 50th Annual Meeting of the American Association for Dental Research (AADR) and the 45th Annual Meeting of the Canadian Association for Dental Research (CADR), on July 21-24, 2021. The oral ulcer is a common oral inflammatory lesion with severe pain but little effective treatment is currently available. Cannabidiol (CBD) is recently emerging as a therapeutic agent for inflammatory diseases. However, the underlying mechanisms are not fully elucidated. Qi and colleagues sought to investigate whether and how CBD could play a therapeutic role in the oral ulcer. Oral ulcer models were performed in the tongue of C57BL/6 mice by acid etching or mechanical trauma, followed by CBD local administration. Samples were harvested for macroscopic and histological evaluation. CBD oral spray on acid- or trauma-induced oral ulcers on mice tongues inhibited inflammation, relieved pain and accelerated lesions closure in a dose-dependent manner. The results show that CBD accelerates oral ulcer healing by inhibiting CMPK2-mediated NLRP3 inflammasome activation and pyroptosis, which is mediated mostly by PPARγ in nucleus and partially by CB1 in plasma membrane. This data may shed light on the development of new therapeutic strategies for oral ulcers.   Algal solution: Could Spirulina modify the microbiome to protect against age-related damage? Louvain Drug Research Institute (Belgium), July 25 2021 Spirulina might help protect against age-related liver inflammation by modifying pathways in the microbiome, say researchers. Consumption of spirulina could help protect against hepatic inflammation in the elderly, according to the new animal research published in Nutrients. Belgian researchers carried out tests on mice, which suggest that the algae Spirulina has an impact on the gut microbiota, which in turn activates the immune system in the gut and improves inflammation in the liver that is associated with ageing. Led by senior author Professor Nathalie Delzenne from the Louvain Drug Research Institute in Belgium, the team said oral feeding of Spirulina was found to modulates several immunological functions involving, among others, the TLR4 pathway in old mice. “The fact that its oral consumption can influence both gut immunity and systemic sites, such as the liver, suggests that its immune action is not confined to the gut immune system,” wrote the team – who said the findings open the way to new therapeutic tools “in the management of immune alterations in aging, based on gut microbe-host interactions.” Furthermore, they suggested that improvement of the homeostasis in the gut ecosystem ‘could be essential' during the aging process, “and, in this perspective, dietary manipulation of the gut microbiota of the elderly with Spirulina, may represent a tool for preserving a healthy gastrointestinal microbial community in addition to its beneficial effects on immune function.” Study details Delzenne and colleagues noted that while the possible cardiovascular and immune support benefits of Spirulina have been fairly widely reported, the new study brings a fresh approach by testing whether the effects could be related to a modulation of gut micrbiota. In the trial, young mice aged three months were fed a standard diet, while older mice aged 24 months were fed a standard diet either with or without 5% Spirulina for six weeks. Upton supplementation with Spirulina, the team reported several changes to gut microbiota composition, including an increase in Roseburia and Lactobacillus populations. “Interestingly, parameters related to the innate immunity are upregulated in the small intestine of Spirulina-treated mice,” said the team. “Furthermore, the supplementation with Spirulina reduces several hepatic inflammatory and oxidative stress markers that are upregulated in old mice versus young mice.” Expression of several genetic and biochemical markers of inflammation and immunity were altered by supplementation with Spirulina, said the team. In particular, the transcription factor Foxp3 – involved in the differentiation of T cells into regulatory T cells (Tregs) – and MCP1 were increased due to Spirulina supplementation in old mice. Old mice that consumed Spirulina also showed activation of several immune parameters including Foxp3 in the ileum – suggesting an improvement of the gut immune function upon Spirulina treatment in this segment, said the Belgian researchers. Furthermore, Spirulina supplementation upregulated both TLR2 and TLR4 expression in the ileum of aged mice. “In accordance with these results, a solution of Spirulina (5%) exhibited a TLR4 agonist activity similar to the one reached in old-SP mice, suggesting a direct effect of the Spirulina, itself, on the TLR4 pathway,” they added. Microbiome mechanisms While the positive effect of Spirulina on the microbiome and liver inflammation is clear, the team noted that the mechanism by which the algae could change the composition of the intestinal microbiota remains unanswered. One possible mechanism could be the presence of antimicrobial substances produced by Spirulina, they said. “On the other hand, antimicrobial peptides (AMPs) could be mediators of the nutritional modulation of the gut microbiota.” “In the present study, RegIIIγ and Pla2g2 were increased by the supplementation with Spirulina, suggesting that the host contributes to the reduction and modification of the microbial community by modulating the production of specific AMPs,” they added.

In this month's EM Quick Hits podcast: Anand Swaminathan on the approach to cardiogenic shock, Hania Bielawska on the myths of radiation dose in pregnant patients, Hans Rosenberg & Michael Gottlieb on PoCUS in airway management, Menaka Pai on VIPIT following AstraZeneca COVID-19 vaccination, Brit Long & Michael Gottlieb on Angiotensin II for emergency clinicians, Michael Schull on tips on the safety of short-term steroid use.... The post EM Quick Hits 28 Cardiogenic Shock, Radiation Dose in Pregnancy, PoCUS in Airway Management, VIPIT, Angiotensin II, Short-Term Steroid Safety appeared first on Emergency Medicine Cases.

Here’s why eating garlic and onions can prevent hypertension and diabetes Federal University of Technology (Nigeria), April 16, 2021 n a recent study, researchers at the Federal University of Technology in Nigeria investigated the benefits of eating garlic, white onion and purple onion against serious conditions like diabetes and hypertension. They confirmed these by looking at how extracts from the three alliums affect the activity of diabetes-related enzymes, such as a-amylase and a-glucosidase, and the hypertension-related enzyme, angiotensin-converting enzyme (ACE). The researchers reported their findings in an article published in the Journal of Dietary Supplements. Garlic, white onion and purple onion show antioxidant, antidiabetic and antihypertensive properties Garlic and onions are spices commonly used in cooking. They also serve as ingredients in several traditional delicacies in Nigeria that are known to contain plenty of polyphenols. To assess the beneficial properties of garlic, white onion and purple onion, the researchers first obtained extracts from each and assessed their inhibitory effects on certain enzymes. They also conducted assays to determine the antioxidant capacities of the extracts. ACE is the enzyme responsible for converting angiotensin I into angiotensin II, the hormone that increases blood pressure, as well as body water and sodium content. Angiotensin II elevates blood pressure by constricting the blood vessels; hence, chemicals that can inhibit the activity of ACE, which is responsible for the production of angiotensin II, are used for the treatment of hypertension. (Related: Meet the “two-day cure” plant: An African medicinal plant that can naturally lower blood pressure.) a-Amylase is the enzyme that breaks down starch and glycogen into glucose and maltose (two glucose molecules bound together). In humans, this enzyme is produced by the salivary glands and the pancreas. a-Glucosidase, on the other hand, is responsible for breaking down carbohydrates in the small intestine and facilitating the absorption of glucose. Inhibiting the activity of this enzyme is one of the strategies currently used to prevent the rise of blood sugar levels following a carbohydrate-filled meal. The researchers reported that the garlic, purple onion and white onion extracts inhibited the activities of ACE, a-amylase and a-glucosidase in vitro in a concentration-dependent manner. At a half maximal inhibitory concentration (IC50) of 0.59 mg/mL, the purple onion extract exhibited a higher inhibitory effect on ACE than the white onion extract (IC50 = 0.66 mg/mL) and the garlic (IC50 = 0.96 mg/mL) extract. Meanwhile, the white onion extract showed a significantly stronger inhibitory effect on a-amylase at an IC50 of 3.93 mg/mL than the garlic extract (IC50 = 8.19 mg/mL) and the purple onion (IC50 = 8.27 mg/mL) extract. The garlic extract, on the other hand, showed a similar inhibitory effect (IC50 = 4.50 mg/mL) on a-glucosidase as the white and purple onion extracts. All three extracts also showed dose-dependent free radical scavenging activity and reducing power in the antioxidant assays. Based on these findings, the researchers concluded that garlic, white onion and purple onion can be used to treat or prevent diabetes and hypertension, thanks to their ability to inhibit ACE, a-amylase and a-glucosidase activity, as well as lipid peroxidation in the pancreas and the heart.   Adolescents with lack of empathy show early signs of psychopathy   University of Coimbra (Portugal), April 14, 2021 A pioneering study with the Portuguese population shows that adolescents with high levels of callous-unemotional traits demonstrate lower levels of anticipated guilt towards the possibility of committing an immoral act and struggle to judge an immoral act as a wrong one. Researchers have evaluated the callous traits, that is, the lack of empathy and disregard for the wellbeing and feelings of others, of 47 adolescents between 15 and 18 years old. The teenagers watched video animations portraying examples of moral transgressions, such as incriminating someone or keeping money that fell from someone else's pocket. "This approach allowed us to create more realistic scenarios that happen in daily life," explains Oscar Gonçalves, a neuroscientist at Proaction Lab and co-author of the study. The adolescents were asked how guilty they would feel if they were the ones to commit the moral transgressions and how wrong they think the actions were.  Although the callous-unemotional traits in adolescents are known to be precursors of psychopathy in adulthood, the results of the study differ from what is known about psychopaths. "Adults with psychopathic traits show low levels of anticipated guilt but consider immoral actions as wrong. However, in our study, adolescents with high CU levels show levels of guilt and judge immoral actions as less wrong," explains Margarida Vasconcelos, first author.  However, researchers have found evidence of a dissociation between moral emotions and moral judgment, that is, between the feelings of guilt and the judgment of immoral actions. "Even in adolescents with sub-clinical levels of callous-unemotional traits, this dissociation typical in psychopathy in adulthood is already happening during development," explains the study coordinator Ana Seara Cardoso.  The results of the study will "contribute to the development of a severe anti-social behavior model" and allow the "development of intervention targets, rehabilitation and early prevention of anti-social behavior," says Ana Seara Cardoso.   Omega-3 supplements do double duty in protecting against stress   Ohio State University, April 20, 2021 A high daily dose of an omega-3 supplement may help slow the effects of aging by suppressing damage and boosting protection at the cellular level during and after a stressful event, new research suggests. Researchers at The Ohio State University found that daily supplements that contained 2.5 grams of omega-3 polyunsaturated fatty acids, the highest dose tested, were the best at helping the body resist the damaging effects of stress. Compared to the placebo group, participants taking omega-3 supplements produced less of the stress hormone cortisol and lower levels of a pro-inflammatory protein during a stressful event in the lab. And while levels of protective compounds sharply declined in the placebo group after the stressor, there were no such decreases detected in people taking omega-3s. The supplements contributed to what the researchers call stress resilience: reduction of harm during stress and, after acute stress, sustained anti-inflammatory activity and protection of cell components that shrink as a consequence of aging. The potential anti-aging effects were considered particularly striking because they occurred in people who were healthy but also sedentary, overweight and middle-aged—all characteristics that could lead to a higher risk for accelerated aging. "The findings suggest that omega-3 supplementation is one relatively simple change people could make that could have a positive effect at breaking the chain between stress and negative health effects," said Annelise Madison, lead author of the paper and a graduate student in clinical psychology at Ohio State. The research is published today (Monday, April 19, 2021) in the journal Molecular Psychiatry. Madison works in the lab of Janice Kiecolt-Glaser, professor of psychiatry and psychology and director of the Institute for Behavioral Medicine Research at Ohio State. This paper is a secondary analysis of one of Kiecolt-Glaser's earlier studies showing that omega-3 supplements altered a ratio of fatty acid consumption in a way that helped preserve tiny segments of DNA in white blood cells. Those short fragments of DNA are called telomeres, which function as protective caps at the end of chromosomes. Telomeres' tendency to shorten in many types of cells is associated with age-related diseases, especially heart disease, and early mortality. In the initial study, researchers were monitoring changes to telomere length in white blood cells known as lymphocytes. For this new study, the researchers looked at how sudden stress affected a group of biological markers that included telomerase, an enzyme that rebuilds telomeres, because levels of the enzyme would react more quickly to stress than the length of telomeres themselves. Specifically, they compared how moderate and high doses of omega-3s and a placebo influenced those markers during and after an experimental stressor. Study participants took either 2.5 grams or 1.25 grams of omega-3s each day, or a placebo containing a mix of oils representing a typical American's daily intake. After four months on the supplements, the 138 research participants, age 40-85, took a 20-minute test combining a speech and a math subtraction task that is known to reliably produce an inflammatory stress response. Only the highest dose of omega-3s helped suppress damage during the stressful event when compared to the placebo group, lowering cortisol and a pro-inflammatory protein by an average of 19% and 33%, respectively. Results from blood samples showed that both doses of omega-3s prevented any changes in telomerase levels or a protein that reduces inflammation in the two hours after participants experienced the acute stress, meaning any needed stress-related cell repair—including telomere restoration—could be performed as usual. In the placebo group, those repair mechanisms lost ground: Telomerase dropped by an average of 24% and the anti-inflammatory protein decreased by an average of at least 20%. "You could consider an increase in cortisol and inflammation potential factors that would erode telomere length," Madison said. "The assumption based on past work is that telomerase can help rebuild telomere length, and you want to have enough telomerase present to compensate for any stress-related damage. "The fact that our results were dose-dependent, and we're seeing more impact with the higher omega-3 dose, would suggest that this supports a causal relationship." The researchers also suggested that by lowering stress-related inflammation, omega-3s may help disrupt the connection between repeated stress and depressive symptoms. Previous research has suggested that people with a higher inflammatory reaction to a stressor in the lab may develop more depressive symptoms over time. "Not everyone who is depressed has heightened inflammation—about a third do. This helps explain why omega-3 supplementation doesn't always result in reduced depressive symptoms," Kiecolt-Glaser said. "If you don't have heightened inflammation, then omega-3s may not be particularly helpful. But for people with depression who do, our results suggest omega-3s would be more useful." The 2.5-gram dose of omega-3s is much higher than what most Americans consume on a daily basis, but study participants showed no signs of having problems with the supplements, Madison said.           Want to be robust at 40-plus? Meeting minimum exercise guidelines won't cut it 5 hours of moderate activity a week may be required to avoid midlife hypertension, UCSF-led study shows University of California at San Francisco, April 15, 2021 Young adults must step up their exercise routines to reduce their chances of developing high blood pressure or hypertension - a condition that may lead to heart attack and stroke, as well as dementia in later life. Current guidelines indicate that adults should have a minimum of two-and-a-half hours of moderate intensity exercise each week, but a new study led by UCSF Benioff Children's Hospitals reveals that boosting exercise to as much as five hours a week may protect against hypertension in midlife - particularly if it is sustained in one's thirties, forties and fifties.  In the study publishing in American Journal of Preventive Medicine on April 15, researchers followed approximately 5,000 adults ages 18 to 30 for 30 years. The participants were asked about their exercise habits, medical history, smoking status and alcohol use. Blood pressure and weight were monitored, together with cholesterol and triglycerides.  Hypertension was noted if blood pressure was 130 over 80 mmHg, the threshold established in 2017 by the American College of Cardiology/American Heart Association.  The 5,115 participants had been enrolled by the Coronary Artery Risk Development in Young Adults (CARDIA) study and came from urban sites in Birmingham, Ala., Chicago, Minneapolis and Oakland, Calif. Approximately half the participants were Black (51.6 percent) and the remainder were White. Just under half (45.5 percent) were men.  Fitness Levels Fall Fast for Black Men Leading to More Hypertension Among the four groups, who were categorized by race and gender, Black men were found to be the most active in early adulthood, exercising slightly more than White men and significantly more than Black women and White women. But by the time Black men reached age 60, exercise intake had slumped from a peak of approximately 560 exercise units to around 300 units, the equivalent to the minimum of two-and-a-half hours a week of moderate intensity exercise recommended by the U.S. Department of Health and Human Services. This was substantially less exercise than White men (approximately 430 units) and slightly more than White women (approximately 320 units). Of the four groups, Black women had the least exercise throughout the study period and saw declines over time to approximately 200 units. "Although Black male youth may have high engagement in sports, socio-economic factors, neighborhood environments, and work or family responsibilities may prevent continued engagement in physical activity through adulthood," said first author Jason Nagata, MD, of the UCSF Division of Adolescent and Young Adult Medicine. Additionally, Black men reported the highest rates of smoking, which may preclude physical activity over time, he noted. Physical activity for White men declined in their twenties and thirties and stabilized at around age 40. For White women, physical activity hovered around 380 exercise units, dipping in their thirties and remaining constant to age 60. Rates of hypertension mirrored this declining physical activity. Approximately 80-to-90 percent of Black men and women had hypertension by age 60, compared with just below 70 percent for White men and 50 percent for White women.  "Results from randomized controlled trials and observational studies have shown that exercise lowers blood pressure, suggesting that it may be important to focus on exercise as a way to lower blood pressure in all adults as they approach middle age," said senior author Kirsten Bibbins-Domingo, MD, PhD, of the UCSF Department of Epidemiology and Biostatistics.  "Teenagers and those in their early twenties may be physically active but these patterns change with age. Our study suggests that maintaining physical activity during young adulthood - at higher levels than previously recommended - may be particularly important." More Exercise from Youth to Midlife Offers Best Protection Against Hypertension When researchers looked at the 17.9 percent of participants who had moderate exercise for at least five hours a week during early adulthood - double the recommended minimum - they found that the likelihood of developing hypertension was 18 percent lower than for those who exercised less than five hours a week. The likelihood was even lower for the 11.7 percent of participants who maintained their exercise habits until age 60.  Patients should be asked about physical activity in the same way as they are routinely checked for blood pressure, glucose and lipid profiles, obesity and smoking, Nagata said, and intervention programs should be held at schools, colleges, churches, workplaces and community organizations. Black women have high rates of obesity and smoking, and low rates of physical activity, he said, and should be an important group for targeted intervention.  "Nearly half of our participants in young adulthood had suboptimal levels of physical activity, which was significantly associated with the onset of hypertension, indicating that we need to raise the minimum standard for physical activity," Nagata said. "This might be especially the case after high school when opportunities for physical activity diminish as young adults transition to college, the workforce and parenthood, and leisure time is eroded."     Study finds association between periodontal disease and low intake of minerals, vitamins and dietary fiber in young adult women Tokyo Medical and Dental University, April 12, 2021 According to news reporting out of Tokyo, Japan, research stated, “Dietary habits of middle-aged and elderly individuals affected by periodontal disease (PD) differ from those who are unaffected by it, according to previous reports. However, in young adults, there are only a few reports that show a correlation between nutrient/food intake and PD.” Our news journalists obtained a quote from the research from Tokyo Medical and Dental University (TMDU), “Moreover, no report till date has assessed the correlation between dietary habits and PD using a self-administered diet history questionnaire (DHQ). Therefore, we assessed this correlation using a DHQ in young adult women who are likely to develop PD. The participants were enrolled from 2 universities and included 120 female college students a mean age of 20.4 y. The participants were assessed for the presence of PD according to the community periodontal index and were divided into two groups, the PD group and the non-PD group. Their dietary habits were investigated using a DHQ and the level of difficulty in chewing food was assessed. The PD group had a significantly lower nutrient intake of minerals, fat-soluble vitamins, water-soluble vitamins, and dietary fiber than the non-PD group. In terms of food groups, the PD group consumed significantly lesser amounts of green and yellow vegetables (GYV) than the non-PD group. Multivariate analysis revealed that the PD group had significantly lower intakes of vitamin E and GYV than the non-PD group. The PD group consumed significantly lesser amounts of hard foods than the non-PD group.” According to the news editors, the research concluded: “Young adult women who were evaluated for PD by a screening test had a significantly lower nutrient/food intake than those without a PD.” This research has been peer-reviewed.       Just 2 days of increased sugar intake can harm your gut health, warn researchers University of Alberta, April 16, 2021 Researchers from the University of Alberta in Canada found that short-term increases in sugar intake can increase the risk of inflammatory bowel disease. Their finding, which was published in Scientific Reports, is a reminder that eating healthy must be sustained in order to keep your gut in good shape. “Surprisingly, our study shows that short-term sugar consumption can really have a detrimental impact, and so this idea that it’s OK to eat well all week and indulge in junk food on the weekend is flawed,” said Karen Madsen, one of the study researchers. Increased sugar intake is bad for the gut Previous studies have shown that diets can affect your susceptibility to disease. Western diets, for example, have been implicated in the development of inflammatory bowel disease. But it’s still unclear when a poor diet begins to take a toll on your health, much less how it does so. To investigate, the researchers placed adult mice on a chow diet or a high-sugar diet and treated them with dextran sodium sulfate to induce ulcerative colitis, one of the major forms of inflammatory bowel disease. Disease severity was assessed daily. After two days, the mice on the high-sugar diet were at great risk of developing colitis. Their immune response also weakened while their gut permeability increased, allowing more bacteria and toxins to enter their bloodstream. “We wanted to know how long it takes before a change in diet translates into an impact on health. In the case of sugar and colitis, it only took two days, which was really surprising to us. We didn’t think it would happen so quickly,” said Madsen. The researchers attributed these effects to sugar’s impact on the gut bacteria. Eating sugary foods decreases the amount of “good” gut bacteria that produce short-chain fatty acids, which are critical for a strong immune response. Meanwhile, sugar feeds “bad” bacteria that promote inflammation and weaken your immunity.  Fortunately, the researchers found that supplementing with short-chain fatty acids helped reduce the negative effects of a high-sugar diet. Having these supplements as an option will be great for people struggling to change their bad eating habits. “People want to eat what they want to eat, so short-chain fatty acids could possibly be used as supplements to help protect people against the detrimental effects of sugar on inflammatory bowel disease,” said Madsen.     Rose water is an antimicrobial and anti-inflammatory remedy for skin infections Teikyo University (Japan), April 15, 2021 Rosa damascena, commonly known as Damask rose, is one of the most important and medicinally useful members of the Rosaceae (rose) family. It is an ornamental plant widely used to make perfumes and is reported to have plenty of beneficial properties. According to multiple studies, Damask rose has anti-HIV, antibacterial, antioxidant, antitussive, hypnotic and antidiabetic properties. It has also shown relaxant effects on the tracheal chains of guinea pigs. In a recent study, researchers at Teikyo University in Japan investigated two biological properties of Damask rose, specifically it’s antimicrobial and anti-inflammatory properties. They tested rose water made from high-quality Damask rose petals on two microbial pathogens, namely, Candida albicans and methicillin-resistant Staphylococcus aureus (MRSA), which commonly cause skin infections. The researchers reported their findings in an article published in Biological and Pharmaceutical Bulletin. Damask rose water is a natural antibiotic and anti-inflammatory agent Damask rose is a multipurpose plant widely known for its culinary and medicinal applications, among other things. Edible parts of Damask rose are used in various cuisines, including its young shoots, petals, fruits, leaves and seeds. Damask rose petals are used to make jams and add flavor to beverages, baked goods and desserts. They are also used for cooking dishes. Rosewater, which can be sweetened to produce rose syrup, is a byproduct of rose oil production. It is usually obtained by steam distilling Damask rose petals and taking the hydrosol portion of the rose petal distillate.  In different parts of the world, rose water, rose oil and a decoction made of Damask rose roots are used in traditional medicine for the treatment of various ailments, such as abdominal and chest pain, digestive problems and inflammation, especially of the neck. In North America, Indian tribes use the decoction as a cough remedy for children. Rose oil is used to treat depression and reduce stress and tension. Inhaling the vapor produced by heating rose oil is also believed to be an effective remedy for allergies, headaches and migraine. Damask rose water, on the other hand, is traditionally used to treat skin conditions, such as erythema (skin redness), itchiness and swelling. To evaluate its antimicrobial and anti-inflammatory properties, the researchers tested Damask rose water against C. albicans and MRSA and assessed its effects on the function of neutrophils, which are white blood cells that serve as key regulators of inflammatory reactions. The researchers reported that Damask rose water (2.2. percent solution) inhibited the mycelial growth of C. albicans and reduced the viability of MRSA within an hour of treatment. Damask rose water (five to 15 percent) also suppressed the activation of neutrophils induced by treatment with lipopolysaccharide (LPS), a bacterial toxin; tumor necrosis factor-alpha (TNF-a), a cell-signaling protein produced by immune cells; and N-formyl-Met-Leu-Phe (fMLP), a macrophage activator. Additionally, Damask rose water reduced LPS- and TNF-a-induced cell surface expression of the adhesion-related molecule, cluster of differentiation 11b (CD11b), which is rapidly elevated by the activation of neutrophils. The amount of CD11b in neutrophils is said to correlate with their activation and inflammation. However, Damask rose water did not affect the migratory capacity of neutrophils (with or without a chemoattractant). Based on these findings, the researchers concluded that Damask rose water can reduce the pathogenicity of microbes and attenuate neutrophil stimulation, thus inhibiting skin inflammation caused by microbial infections.     Study shows how chronic stress may inhibit the body's cancer-fighting ability University of Western Ontario, April 15, 2021 New research from Western University has shown how psychological stress hinders the immune system's defenses against cancer. By investigating the effects of chronic stresson the immune system's "emergency responders," researchers at the Schulich School of Medicine & Dentistry found that a stress-induced hormone impairs the ability of these immune cells to carry out their cancer-fighting function. Led by Mansour Haeryfar, Ph.D., the research looked specifically at innate-like T cells, which when functioning properly enable the immune system to look for potentially cancerous cells in the body and destroy them. The study was published today in Cell Reports. Innate-like T cells include invariant natural killer T (iNKT) and mucosa-associated invariant T (MAIT) cells, which were the subjects of this investigation. iNKT cells are present in small numbers in many tissues but are especially enriched in the human omentum, an apron-like layer of fatty tissue. MAIT cells are present in relatively high numbers in the human peripheral blood, gut, lungs and liver among other organs. "These innate-like T cells are our immune system's emergency responders," said Haeryfar. "They react quickly to pathogens and cancer cells and are in a pre-activated mode, so they are like loaded guns, ready to respond." Previous studies have shown that when a person experiences chronic psychological and emotional stress, the body's immune system is suppressed, dampening its ability to fight cancer and opportunistic infections. This happens in large part because stress hormones kill off some of the body's immune cells. However, Haeryfar and his team showed that innate-like T cells actually don't die as a result of chronic stress but their cancer-fighting abilities are drastically impaired by stress-induced hormones called glucocorticoids. This impairment led to a striking increase in cancer metastasis in a mouse model. "We found that innate-like T cells survive when the host is under stress, but their functions are compromised," Haeryfar said. "The cells cannot make enough of their beneficial mediators to help fight cancer, so the metastatic burden is increased because of the stress." The team also looked at the effects of natural and synthetic glucocorticoids on innate-like T cells in human blood and liver tissue, where they are abundant. This was important to providing initial evidence that some of the discoveries made in the mouse models were valid for human cells as well, said Patrick Rudak, Ph.D. Candidate in Haeryfar's lab. One of the important implications of this work is that innate-like T cells are currently being investigated for cancer immunotherapy treatment. This study demonstrates that their therapeutic potential can be dampened by psychological stress, said Haeryfar, and this finding needs to be considered when designing or administering those therapies. Rudak added: "Our study demonstrates that, despite being capable of instigating robust anti-tumor immune responses under normal conditions, innate-like T cells completely fail to protect against tumors during psychological stress." Because the study also uncovered the mechanisms by which stress diminishes T cell function, the researchers hope they can use the information to help design immunotherapies involving these cells that will still be effective in psychologically stressed patients.

Join your host, John Prevost as we reboot this Health Journey the RIGHT way!! I promised myself last year to be consistent and I failed to do so, although, I only have one year left at PALMER college of chiropractic so I decided late is better than never. If you enjoy this episode about who I am and how I feel about what is happening in the world right now, then stay tuned for part 2!! Remember I am just a student trying to think logically through this world, my brain is always open for enlightenment.. This is not medical advice please seek your PCP for medical advice. As always do your own DD and research, research, research!! What is discussed in this episode: Who am I?What is Health Sucks about?What is Health?What is SARS-COV2? What is Systems Approach?Why a Health Problem and NOT a viral one? REFERENCES: - Seaman D. The Deflame Diet for Immune Health. Shadow Panther Press , 25 January 2021-CDC website: People who are at higher risk for severe illness. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-at-higher-risk.html-Zumla A, Maeurer M. Host-directed therapies for tackling multi-drug resistant tuberculosis: learning from the Pasteur-Bechamp debates. Clin Infect Dis. 2015: 61:1432-38-Verdecchia P, Cavallini C, Sapnevellow A, Angeli F. The pivotal link between ACE2 deficiency and SARS-COV-2 infection. Eur J Intern Med. April 20, 2020-Ceriello A. Hyperglycemia and the worse prognosis of COVID-19. why a fast glucose control should be mandatory. Diabetes Res Clin Pract. 2020; 163:108186.-Illi PC, Stefanescu S, Smith L. The role of Vitamin D in the prevention of corona virus disease 2019 infections and mortality. Aging Clin Exper Res. 2020; May 6:1-4. - Phillips MI,  Kagiyama S. Angiotensin II as a pro-inflammatory mediator. Curr Opin Investig Drugs. 2002; 3:569-77. - https://youtu.be/ha2mLz-Xdpg - https://youtu.be/oA-fTaGadyc-https://youtu.be/OY8QV7lnFFo

Back by popular demand…all two of you…the second chapter of The Clinical Physiology of Acid Base and Electrolyte Disorders. Chapter Outline- Renal Circulation and GFR - RBF is 20% of cardiac output - In terms of mL per 100 g organ weight it is 4x the liver and exercising muscle and 8x coronary blood flow! - After the glomeruli the efferent arteriole have two fates - Peritubular capillaries in the cortex - Peritubular capillaries are not necessarily associated with their parent glomeruli. Weird. - Vasa recta from juxtamedullary glomeruli in the medullaJoel Says: This seems wrong. Solute balance can be maintained down to a very low GFR. The R^2 here would be very low. Prove me wrong. - States that GFR is an important determinant of solute and water excretion. - Glomerular anatomy and function - Structure Four editions of the Bud Bible up top and a copy of Bud Light on the bottom. - Glomerulus is a tuft of capillaries - Enclosed in a capsule of epithelial cells, called Bowman's capsule - The epithelial cells of Bowman's capsule are continuous with the epithelial cells of the proximal tubule Looking at scanning EMs of the glomerulus is one of life's simple pleasures—Josh. Josh says: Look at the review in Nature Reviews Nephrology from Rachel Lennon's groupComplexities of the glomerular basement membrane - Filtration barrier - Epithelial cell (podocyte) - Epithelial cells adhere to the basement membrane via foot processes and the foot processes have slit diaphragms - Basement membrane New Super-resolution structure of the GBM: https://elifesciences.org/articles/01149 Hi res microscopy is really hi-res. Technique is call ed STORM. Melanie talks about conduits through the glomeruli. Here is a cool review: Why until just now? Undiscovered uniqueness of the human glomerulus! by L. Gabriel Navar, Owen RichfieldAm J Physiol Renal Physiol. 2018 Nov 1; 315(5): F1345–F1346. Published online 2018 Aug 15. doi: 10.1152/ajprenal.00369.2018 PMCID: PMC6293291 - Produced by both the endothelial cells and podocytes - Formed from type IV collagen - Abnormalities of type 4 collagen cause Alport - The gene coding for the alpha 5 chain is the culprit - COL4A5 - Abnormal Alpha 3 and 4 chains can also cause hereditary nephritis - Has other substances - Laminin - Nidogen - Heparin sulfate proteoglycans - Provides the negative charge - Enthothelial cell (fenestrated) - Protein excretion - Glomerular function: allow filtration of small solutes (Na and urea) while preventing filtration of larger molecules - Insulin MW 5,200 is freely filtered (upper range of freely filtered) - Preventing loss of protein prevents - Negative nitrogen balance - Development of hypoalbuminemia - Infection from loss of immunoglobulin - Size and charge selectivity of the GBM - pores are between cords of type 4 collagen - The epithelial cells and slit diaphragms matter - Macromolecules that pass through GBM can accumulate underneath the epithelial layer - Isolated GBM in invitro studies is much more permeable to than intact glomerulus - There is increased protein filtration in areas where the epithelial cells have detached from the GBM Josh really likes this figure from another Nature Reviews Nephrology paper. This one by Moeller and Chia-Gil. - Mutations in nephrin, localized to the slit diaphragm causes congenital nephrotic syndrome - Charge selectivity is important - Neutral and cationic particle are more likely to be filtered - Albumin (negative charge) is filtered 5% as well as same size neutral dextrans - In glomerular disease, while there is increased filtration of proteins there is decreased filtration of small solutes due to loss of glomerular surface areaJC says: Take a look at this research on the serving coefficient in glomerular disease. Some surprising results.Glomerular dysfunction in nephrotic humans with minimal changes or focal glomerulosclerosis - Why do people in remission have what appears to be spilling more high molecular radius particles than normal and why do patients with active MCD have lower clearance across all molecular diameters? - Other glomerular functionsJosh says: Take a look at this interesting paper by Butt et alA molecular mechanism explaining albuminuria in kidney disease - Synthetic - Epithelial cells produce GBM - Phagocytic - Remove circulating macromolecules that pass through GBM and get trapped in subepithelial spaceJosh says: The sFLT1 (soluble VEGF receptor) relationship to preeclampsia is just so cool. And here's the paper:Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsiaAnd in the NEJM: VEGF Inhibition and Renal Thrombotic Microangiopathy - Endocrine - Enthothelial cells regulate vascular tone by releasing - Prostacyclin - Endothelin - Nitric oxideJC says: Do yourself a favor and spend some time learning about extraglomerular mesangial cells with Stuart Shankland Extraglomerular origin of the mesangial cell after injury. A new role of the juxtaglomerular apparatusJoel adds, if you ever get a chance to party with Dr. Shankland, don't skip out. - Mesangial cells, two types - Intrinsic Mesangial cell - Microfilaments similar to smooth muscle - Responds to Ang2 - Regulates glomerular hemodynamics - Can release cytokines - Can respond to cytokines by proliferation - Circulating macrophages and monocytes - Phagocytic function - Clear molecules that get through the endothelial wall but cant get through the GBMJosh says, “Topf, get it right. Its Ree-nin not renin. Classic letter to JAMA. - Renin-Angiotensin System - Afferent arteriole contain specialized cells called juxtaglomerular cells - Produce prorenin which cleaved into renin - Stimuli for renin release - Hypotension - Volume depletion - Increased sympathetic activity - Renin catalyze the production of ang1 from angiotensinogen - Ang1 is catalyze to Ang2 by ACE located in the - Lung - Endothelial cells - Glomeruli itself pic.twitter.com/DaDfS7u8se— Roger Rodby (@NephRodby) February 22, 2021 - Discussion of local renin and Aniotensinogen - Explains why ACEi are useful even with low systemic renin levels and Ang2 - Actions of Ang2 - Sodium and water retention - By direct Na reabsorption in the early PT (and in the proximal tubule, water is permeable to the epithelium so every sodium reabsobed, brings a water molecule along for the osmotic ride. - Stimulates the Na-H antiporter - 40-50% of Na reabsorption in the S1 segment of the PT is due to Ang2 - By stimulation of aldosterone - Ang2 that stimulates Aldo comes from the kidney and from the adrenal gland itself - VasoconstrictionJosh talks angiotensin:Tenses the angios--love this Melanie!1961 paper from del Greco (who's endowed chair Dan Batlle has now) trying AT2 in "hopeless" patients and dialysis patients:https://jamanetwork.com/journals/jama/article-abstract/332265Great EM-crit/pulmcrit discussion here:https://emcrit.org/emcrit/deeper-vasopressors-athos-3/and caveats here:https://emcrit.org/pulmcrit/angiotensin-ii/ - Arteriolar vasoconstriction - Ang2 important for raising BP in RAS - Ang2 important in maintaining BP with volume depletion or in CHF, liver disease - Giving ACEi to cirrhosis can cause BP to dump 25 points - Regulation of GFR - Affects constriction at afferent arteriole and efferent arteriole - Mediated via thromboxane JC talks about the ATHOS trial and how there is a signal for improved outcomes especially in patients requiring renal replacement therapy.Angiotensin II for the Treatment of Vasodilatory ShockOutcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II - Afferent arteriole starts bigger so reductions have less of an effect than constriction does on the narrower efferent arteriole. - This results in a fall of RBF due to increased resistance but maintaining GFR by increasing inrtaglomerular pressure. - Also stimulates prostaglandins which are vasodilator, modulating this affectJoel says: You haven't heard of the Trolly Problem? Oh you need to take 5 minutes and read this. - It can stimulate contraction of the mesangium reducing surface area of the glom reducing filtration. - It sensitizes the afferent arteriole to TG feedback so it can reduce glomerular flow in response to increased chloride detection in the TLoH. - Control of renin secretionEver wanted to know about intrarenal renin concentrations? Yeah, me neither. But JC's got you covered: Endogenous angiotensin concentrations in specific intrarenal fluid compartments of the rat. - Primarily sodium intake, increased intake results in less renin - Mediated by baroreceptors - Baroreceptors in afferent vessel wall - Cardiac and arterial baroreceptors which activate the sympathetic nervous system and catecholamines which then stimulates reninRoger says: Do your self a favor and read about Yanomamo IndiansBlood pressure and electrolyte excretion in the Yanomamo Indians, an isolated population - Cells of the macula densa in the early distal tubule which detect decreased chloride delivery - This allows loop diuretics to be particularly effective at increasing renin as they block chloride resorption - Suppression of renin in response to chloride is mediated by adenosine - Stimulation of renin in response to decreased chloride is mediated by PGE - The PGE cause local vasodilation so the kidney maintained a rich blood flow while using renin and Ang2 to cause systemic vasoconstrictionAnna's notes for the deep dive in glomerular barrierOur understanding is based on technology available at the time. Even in 1920s, there was thought that tubular reuptake of protein may be important, but studies never demonstrated this til 2007 and even then are debated. 2007 Russo, et al (and BM at IU!) showed that The normal kidney filters nephrotic levels of albumin and that failure of retrieval by proximal tubule cells is what separates proteinuria from nonproteinuria. This was countered by a study in 2009 demonstrating much lower GSC and suggesting that the high GSC in the 2007 could be the result of nonphysiologic states.Check out this 2008 debate in JASN regarding the validity of the charge model and “normal” albumin in the glomerular filtrate. Hotly debated with too many studies to cite. 2017: Lawrence et al publish their findings that the GBM and podocyte processes are sufficient and the slit diaphragm likely does not exist. They used labeled proteins and confocal microscopy to determine migration of particles through the enodthelium and GBM. They also injected NaSCN oligoclusters from the size of albumin (66kDa)up to the size of IgG dimers (300 kDa) into mice, then fixed. The size-sensitive permeation into the lamina densa of the GBM and the podocyte glycocalyx of albumin and uptake of any “escaping” albumin by the proximal tubule was also observed. This countered the common prior conception that the slit diaphragms pores are the site of albumin “capture.” For your reading pleasure the review of Clinical Physiology of Acid-Base and Electrolyte Disorders Fourth Edition in Annals of Internal Medicine

I have admittedly zero clinical experience with angiotensin II/Giapreza. My colleague Rishi Kumar, MD explains how he uses Giapreza in his practice. Check out Rishi's website: rk.md Follow him on Instagram: www.instagram.com/rishimd Follow him on Twitter: www.twitter.com/rishikumarmd Check out his videos on YouTube: www.youtube.com/RishiKumarMD Show Notes: https://eddyjoemd.com/vasopressors/ Receive a FREE audiobook (TWO for Amazon Prime members) with your FREE 30-day trial by using my link for Audible: CLICK HERE! You will be reminded when your trial is ending, by the way.

Reviewing a new article published in this month's issue of CHEST looking at the safety and effectiveness of angiotensin II in patients with shock of differing etiologies. Show Notes: https://eddyjoemd.com/vasopressors/ Receive a FREE audiobook (TWO for Amazon Prime members) with your FREE 30-day trial by using my link for Audible: CLICK HERE! You will be reminded when your trial is ending, by the way.

Dr. Rosenberg has been involved with drug research since 1991. Having studied the mechanisms of cancer treatment failure, the following concept has become blatantly apparent to Dr. Rosenberg.   There are many substances that are toxic to cancer cells in vitro (outside of the body, in a culture medium), including chemotherapy and intravenous antioxidant therapy. These therapies, however, are more often then not, ineffective in vivo (inside the body). The primary reason for the ineffectiveness is that tumor blood flow is poor, resulting in a tumor that actually receives very little of the cytotoxic therapy that is being administered. In addition, poor tumor blood flow is associated with higher grade tumors and greater incidence of metastasis.   Dr. Rosenberg has since concentrated his efforts on improving blood flow to the cancer, while administering cytotoxic intravenous antioxidant therapy. In addition to using vasodilating therapy such as carbogen and isosorbide dinitrate, Dr. Rosenberg has just been granted approval status for an IND (investigational new drug) using Angiotensin II. Angiotensin II is frequently used in Japan in conjunction with chemotherapy to improve tumor blood flow.   Dr. Rosenberg recently appeared on Fox News in 2006, for inducing remission on a patient with metastatic lung cancer (to liver and spine) that was refractory to chemotherapy.  

It’s the JournalFeed Podcast for the week of Dec 21-25, 2020. We cover the pros and cons of NSAIDs for adult fractures, the accuracy of COVID-19 antibody testing, angiotensin II for refractory shock, and a Merry Christmas song!

In this episode, we highlighted how the body system balances it's fluid in constancy through the following; 1) hormones ( Aldosterone, Atrial natriuretic peptide-ANP, Angiotensin II and Parathyroid hormone) , 2) Water balance, 3) pH(acid-base) balance. --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app --- Send in a voice message: https://anchor.fm/oge-osondu/message

In this 5 minute bit we discuss Phenylephrine, Angiotensin II, Dobutamine and Milrinone. Please see attached evidence related to our topic:*Just to clarify, dobutamine and milrinone can both be used for right ventricular systolic failure but there is some evidence that milrinone may provide better pulmonary vascular afterload reduction than dobutamine. NO MILRINONE IN RENAL FAILURE. MILRINONE IS LONG ACTING. *Just to clarify, Angiotensin II data was not solely tested against placebo. The actual randomized trial had both groups on high dose norepinephrine and one group had placebo as a second agent and the other group had angiotensin II as a second agent. The point of the trial was to demonstrate Angiotensin II efficacy in a patient that was failing high dose norepinephrine alone (or equivalent dose of another vasopressor). So the trial was not really Angiotensin II against just placebo as both groups were also on high dose catecholamine.https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0534-9https://www.nejm.org/doi/full/10.1056/NEJMoa1704154https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764562/https://www.ncbi.nlm.nih.gov/books/NBK470431/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691094/https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-14/Treatment-of-right-heart-failure-is-there-a-solution-to-the-problem

FDA 批准血管紧张素II用于休克病人低血压的治疗NEJM 秋水仙碱在慢性冠心病患者中的疗效Circulation 心脏内源性干细胞和心肌细胞增殖的争论、谬误和进展血管紧张素II（angiotensin II）2017年12月，FDA批准合成人血管紧张素II用于治疗分布性休克患者。《ATHOS-3研究：血管紧张素II治疗血管舒张性休克的3期临床研究》New England Journal of Medicine，2017年8月 (1)血管舒张性休克的患者对高剂量的血管收缩剂反应差，而且会增加死亡率。此研究的目的是评价这类患者使用血管紧张素II的疗效。研究纳入需要大剂量血管收缩药物维持血压的、血管舒张性休克的患者344人（去甲肾上腺素用量>0.2μg/kg/min或等剂量的血管收缩药），随机分入血管紧张素II治疗组和安慰剂组。用药3小时后，血压升高10mmHg或平均血压升高至75mmHg的患者，干预组达到69.9%，安慰剂组只有23.4%（P0.2）或高血压显著升高的情况（P>0.2）。结论：卡那单抗虽然可降低主要心血管事件发生率，但这些获益与血压变化无关。《COLCOT研究：小剂量秋水仙碱治疗心肌梗死的疗效和安全性》New England Journal of Medicine，2019年11月 (6)秋水仙碱是一种口服的，有效的抗炎药物，是用于治疗痛风和心包炎。研究的目的是评价秋水仙碱抗炎治疗近期心肌梗死患者对缺血性心血管事件的影响。研究招募了急性心肌梗死30天内的患者共4745人，随机分到秋水仙碱 0.5mg qd组或安慰剂。平均随访22.6个月后，秋水仙碱组和安慰剂组分别有5.5%和7.1%的患者出现主要终点事件（心血管原因死亡、心脏骤停复苏、心肌梗死、卒中或因心绞痛紧急住院导致冠状动脉血运重建）（P = 0.02）。与安慰剂相比，秋水仙碱心血管原因死亡的风险比0.84，心脏骤停风险比0.83，心肌梗死风险比为0.91；能显著降低卒中的风险达74%，同时能显著降低心绞痛住院再次血运重建的风险达50%。两组最常见的不良事件是腹泻，发生率没有差异，最严重的不良事件是肺炎，发生率分别为0.9%和0.4%（P = 0.03）。结论：在近期心肌梗死患者中，每天0.5 mg的秋水仙碱比安慰剂显著降低缺血性心血管事件的风险。《COLCOT研究：秋水仙碱治疗起始时间与心肌梗死后心血管预后的关系》European Heart Journal，2020年8月 (7)这项COLCOT研究的分析，纳入了4661例患者，按照启动秋水仙碱治疗距离急性心肌梗死的时间可分为三个亚组，8天组。平均随访22.7个月后，8天组没有统计学意义（风险比 0.96和0.82）。不仅如此，3天内启动秋水仙碱治疗的患者，心绞痛住院血运重建术的风险显著降低（风险比 0.35）、再次血运重建风险显著降低（风险比 0.63），而且所有的复合心血管死亡、心脏骤停、心肌梗死或卒中的风险均显著降低（风险比 0.55，P < 0.05)。结论：心肌梗死后，患者应尽早在医院内给予秋水仙碱治疗。《LoDoCo2研究：秋水仙碱在慢性冠心病患者中的疗效》New England Journal of Medicine，2020年8月(8)秋水仙碱的抗炎作用可降低近期心肌梗死患者发生心血管事件的风险，但对慢性冠心病患者的证据有限。这项随机、对照、双盲试验中，招募5522名慢性冠心病患者，随机分配至秋水仙碱0.5mg qd组或安慰剂组，平均随访时间为28.6个月。主要终点事件（心血管死亡、自发心肌梗死、缺血性卒中或缺血驱动的冠状动脉血运重建）在秋水仙碱组和安慰剂组的发生率分别为6.8%和9.6%（P < 0.001)。次要终点事件（心血管死亡、自发心肌梗死、缺血性卒中）在秋水仙碱组和安慰剂组的发生率分别为4.2%和5.7%（P = 0.007）。秋水仙碱组的自发性心肌梗死或缺血驱动的冠脉血运重建的复合终点、心血管死亡或自发性心肌梗死的复合终点、缺血驱动的冠脉血运重建和自发性心肌梗死的发生率也显著降低。秋水仙碱组的非心血管疾病死亡发生率高于安慰剂组（风险比 1.51）。结论：秋水仙碱可以显著降低慢性冠心病患者发生心血管事件的风险。小羽点评：冠心病发病机制复杂，不仅限于胆固醇内膜浸润，也是免疫系统的全身和局部激活驱动的血管壁的慢性炎症的结果，最终导致斑块破裂或侵蚀、血栓形成、心肌梗死。在广泛使用他汀类药物后，仍有大量患者出现复发，反映了残留炎症并没有被充分控制。现在抗炎药物治疗成为热点，但是否能上升到一线治疗的地位，我们拭目以待。心脏干细胞修复技术《综述：心脏内源性干细胞和心肌细胞增殖的争论、谬误和进展》Circulation，2020年7月 (9)在过去的十年里，许多类型的心脏干细胞（CSCs）从实验室到临床研究，但并有什么确切的治疗效果。有关干细胞示踪的基础研究开始质疑心脏干细胞的基础生物学和作用机制，挑战心脏干细胞的起源和存在。除了心脏干细胞在心脏再生中的潜在作用外，现有心肌细胞的增殖得到了更多的关注。中国科学院研究人员发表的这篇综述评估了过去和现在关于心脏干细胞和心肌细胞增殖的研究的方法和技术方面，也讨论了潜在局限性。作者认为未来的研究方向：（1）由于缺乏常驻CSC存在的证据，内源性心肌细胞增殖频率又非常低，如何促进心肌细胞增殖可能是未来一个重要的研究领域；（2）除了诱导心肌细胞增殖外，还可以考虑其他替代方法，比如通过过表达特定转录因子、或小分子诱导的方式，使成纤维细胞原位重新编程成为心肌细胞，如此使心肌细胞再生同时减少瘢痕形成；（3）人胚胎干细胞或诱导多潜能细胞来源的心脏祖细胞和心肌细胞已成功移植到大型动物模型中，并已证实了移植细胞在宿主心肌内的存活和心脏功能的改善；（4）即使没有直接的心肌细胞再生，促进新血管形成的方法，如通过移植能够分泌血管生长因子的间充质干细胞，或减轻心肌梗死后炎症损伤等方法，来改善心肌存活率、减少疤痕形成；（5）双重干细胞疗法协同改善心肌损伤后心脏功能和血管新生，如人类诱导性多潜能干细胞来源的心肌细胞和间充质干细胞，或人类胚胎干细胞来源的心外膜细胞和心肌细胞；（6）含有生长因子或多种心脏细胞类型的心外膜贴片，也被证明可以改善心肌梗死后的心脏功能和新生血管；（7）通过RNA修饰心外膜祖细胞后产生的血管内皮生长因子A可以使血管再生增强；最后，作者认为，由于内源性假定心脏干细胞的错误，因此，为达到心脏修复和再生的最终目标，应该将更多的精力和资源投入到更有前途的方向上是很重要的。《综述：对胚胎干细胞在心脏修复中的作用的评价》European Heart Journal，2020年7月 (10)尽管胚胎干细胞（ESCs）具有分化为心肌细胞的能力，胚胎干细胞或胚胎干细胞来源的细胞的移植仍面临着一些非常棘手的问题：（1）移植物排斥反应，通过药物诱导免疫抑制本身就是一种疾病；（2）心律失常，研究发现在灵长类动物中移植人类胚胎干细胞来源的细胞会导致危及生命的心律失常，而这种心律失常的发生与剂量无关；（3）恶性肿瘤，在当代临床研究中，对恶性肿瘤等灾难性影响的耐受限度为零。尽管胚胎干细胞分化成肿瘤的可能性非常低，但不是完全没有可能，特别是移植细胞的数量级在十亿的时候；（4）长期再生能力，虽然胚胎干细胞和胚胎干细胞来源的细胞被吹捧为具有长期再生能力，但干细胞示踪技术显示这些细胞在移植后迅速消失，没有长期移植或再生的证据；（5）越来越多的证据表明胚胎干细胞的作用是通过旁分泌机制来发挥的，尚没有开展或启动胚胎干细胞来源细胞在心血管疾病中的临床对照试验；作者最后对未来发展的方向做了预估：（1）成年细胞已用于数千名心脏病患者，没有显著的副作用，其结果令人鼓舞，值得进行II期和III期试验。（2）人诱导的多潜能干细胞提供类似胚胎干细胞的多能性，而不需要终身免疫抑制。《COVID-19患者中使用秋水仙碱治疗对心脏、炎症指标及临床预后的影响》JAMA Network Open，2020年6月 (11)研究旨在比较秋水仙碱和标准化治疗对心脏、炎症指标及临床预后的影响。在105例随机临床试验中，秋水仙碱干预组在常规治疗的基础上，首剂1.5mg，如果没有观察到胃肠道不良反应则60分钟后再给0.5mg，维持剂量为0.5mg qd（体重60kg）直至出院或满21天。对照组的主要临床终点、临床恶化率高于秋水仙碱组，而且对照组患者出现恶化比较快。两组高敏肌钙蛋白浓度无差异，但秋水仙碱组患者D-二聚体的增幅较小。结论：秋水仙碱对COVID-19由一定的治疗作用。参考文献1.Khanna A, Ostermann M, Bellomo R. 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Hypertension. 2020;75(2):477-82.6.Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019;381(26):2497-505.7.Bouabdallaoui N, Tardif JC, Waters DD, Pinto FJ, Maggioni AP, Diaz R, et al. Time-to-treatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT). Eur Heart J. 2020.8.Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, et al. Colchicine in Patients with Chronic Coronary Disease. New England Journal of Medicine. 2020.9.He L, Nguyen NB, Ardehali R, Zhou B. Heart Regeneration by Endogenous Stem Cells and Cardiomyocyte Proliferation. Circulation. 2020;142(3):275-91.10.Wysoczynski M, Bolli R. A realistic appraisal of the use of embryonic stem cell-based therapies for cardiac repair. Eur Heart J. 2020;41(25):2397-404.11.Deftereos SG, Giannopoulos G, Vrachatis DA, Siasos GD, Giotaki SG, Gargalianos P, et al. Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial. JAMA Network Open. 2020;3(6):e2013136-e.

FDA 批准血管紧张素II用于休克病人低血压的治疗NEJM 秋水仙碱在慢性冠心病患者中的疗效Circulation 心脏内源性干细胞和心肌细胞增殖的争论、谬误和进展血管紧张素II（angiotensin II）2017年12月，FDA批准合成人血管紧张素II用于治疗分布性休克患者。《ATHOS-3研究：血管紧张素II治疗血管舒张性休克的3期临床研究》New England Journal of Medicine，2017年8月 (1)血管舒张性休克的患者对高剂量的血管收缩剂反应差，而且会增加死亡率。此研究的目的是评价这类患者使用血管紧张素II的疗效。研究纳入需要大剂量血管收缩药物维持血压的、血管舒张性休克的患者344人（去甲肾上腺素用量>0.2μg/kg/min或等剂量的血管收缩药），随机分入血管紧张素II治疗组和安慰剂组。用药3小时后，血压升高10mmHg或平均血压升高至75mmHg的患者，干预组达到69.9%，安慰剂组只有23.4%（P0.2）或高血压显著升高的情况（P>0.2）。结论：卡那单抗虽然可降低主要心血管事件发生率，但这些获益与血压变化无关。《COLCOT研究：小剂量秋水仙碱治疗心肌梗死的疗效和安全性》New England Journal of Medicine，2019年11月 (6)秋水仙碱是一种口服的，有效的抗炎药物，是用于治疗痛风和心包炎。研究的目的是评价秋水仙碱抗炎治疗近期心肌梗死患者对缺血性心血管事件的影响。研究招募了急性心肌梗死30天内的患者共4745人，随机分到秋水仙碱 0.5mg qd组或安慰剂。平均随访22.6个月后，秋水仙碱组和安慰剂组分别有5.5%和7.1%的患者出现主要终点事件（心血管原因死亡、心脏骤停复苏、心肌梗死、卒中或因心绞痛紧急住院导致冠状动脉血运重建）（P = 0.02）。与安慰剂相比，秋水仙碱心血管原因死亡的风险比0.84，心脏骤停风险比0.83，心肌梗死风险比为0.91；能显著降低卒中的风险达74%，同时能显著降低心绞痛住院再次血运重建的风险达50%。两组最常见的不良事件是腹泻，发生率没有差异，最严重的不良事件是肺炎，发生率分别为0.9%和0.4%（P = 0.03）。结论：在近期心肌梗死患者中，每天0.5 mg的秋水仙碱比安慰剂显著降低缺血性心血管事件的风险。《COLCOT研究：秋水仙碱治疗起始时间与心肌梗死后心血管预后的关系》European Heart Journal，2020年8月 (7)这项COLCOT研究的分析，纳入了4661例患者，按照启动秋水仙碱治疗距离急性心肌梗死的时间可分为三个亚组，8天组。平均随访22.7个月后，8天组没有统计学意义（风险比 0.96和0.82）。不仅如此，3天内启动秋水仙碱治疗的患者，心绞痛住院血运重建术的风险显著降低（风险比 0.35）、再次血运重建风险显著降低（风险比 0.63），而且所有的复合心血管死亡、心脏骤停、心肌梗死或卒中的风险均显著降低（风险比 0.55，P < 0.05)。结论：心肌梗死后，患者应尽早在医院内给予秋水仙碱治疗。《LoDoCo2研究：秋水仙碱在慢性冠心病患者中的疗效》New England Journal of Medicine，2020年8月(8)秋水仙碱的抗炎作用可降低近期心肌梗死患者发生心血管事件的风险，但对慢性冠心病患者的证据有限。这项随机、对照、双盲试验中，招募5522名慢性冠心病患者，随机分配至秋水仙碱0.5mg qd组或安慰剂组，平均随访时间为28.6个月。主要终点事件（心血管死亡、自发心肌梗死、缺血性卒中或缺血驱动的冠状动脉血运重建）在秋水仙碱组和安慰剂组的发生率分别为6.8%和9.6%（P < 0.001)。次要终点事件（心血管死亡、自发心肌梗死、缺血性卒中）在秋水仙碱组和安慰剂组的发生率分别为4.2%和5.7%（P = 0.007）。秋水仙碱组的自发性心肌梗死或缺血驱动的冠脉血运重建的复合终点、心血管死亡或自发性心肌梗死的复合终点、缺血驱动的冠脉血运重建和自发性心肌梗死的发生率也显著降低。秋水仙碱组的非心血管疾病死亡发生率高于安慰剂组（风险比 1.51）。结论：秋水仙碱可以显著降低慢性冠心病患者发生心血管事件的风险。小羽点评：冠心病发病机制复杂，不仅限于胆固醇内膜浸润，也是免疫系统的全身和局部激活驱动的血管壁的慢性炎症的结果，最终导致斑块破裂或侵蚀、血栓形成、心肌梗死。在广泛使用他汀类药物后，仍有大量患者出现复发，反映了残留炎症并没有被充分控制。现在抗炎药物治疗成为热点，但是否能上升到一线治疗的地位，我们拭目以待。心脏干细胞修复技术《综述：心脏内源性干细胞和心肌细胞增殖的争论、谬误和进展》Circulation，2020年7月 (9)在过去的十年里，许多类型的心脏干细胞（CSCs）从实验室到临床研究，但并有什么确切的治疗效果。有关干细胞示踪的基础研究开始质疑心脏干细胞的基础生物学和作用机制，挑战心脏干细胞的起源和存在。除了心脏干细胞在心脏再生中的潜在作用外，现有心肌细胞的增殖得到了更多的关注。中国科学院研究人员发表的这篇综述评估了过去和现在关于心脏干细胞和心肌细胞增殖的研究的方法和技术方面，也讨论了潜在局限性。作者认为未来的研究方向：（1）由于缺乏常驻CSC存在的证据，内源性心肌细胞增殖频率又非常低，如何促进心肌细胞增殖可能是未来一个重要的研究领域；（2）除了诱导心肌细胞增殖外，还可以考虑其他替代方法，比如通过过表达特定转录因子、或小分子诱导的方式，使成纤维细胞原位重新编程成为心肌细胞，如此使心肌细胞再生同时减少瘢痕形成；（3）人胚胎干细胞或诱导多潜能细胞来源的心脏祖细胞和心肌细胞已成功移植到大型动物模型中，并已证实了移植细胞在宿主心肌内的存活和心脏功能的改善；（4）即使没有直接的心肌细胞再生，促进新血管形成的方法，如通过移植能够分泌血管生长因子的间充质干细胞，或减轻心肌梗死后炎症损伤等方法，来改善心肌存活率、减少疤痕形成；（5）双重干细胞疗法协同改善心肌损伤后心脏功能和血管新生，如人类诱导性多潜能干细胞来源的心肌细胞和间充质干细胞，或人类胚胎干细胞来源的心外膜细胞和心肌细胞；（6）含有生长因子或多种心脏细胞类型的心外膜贴片，也被证明可以改善心肌梗死后的心脏功能和新生血管；（7）通过RNA修饰心外膜祖细胞后产生的血管内皮生长因子A可以使血管再生增强；最后，作者认为，由于内源性假定心脏干细胞的错误，因此，为达到心脏修复和再生的最终目标，应该将更多的精力和资源投入到更有前途的方向上是很重要的。《综述：对胚胎干细胞在心脏修复中的作用的评价》European Heart Journal，2020年7月 (10)尽管胚胎干细胞（ESCs）具有分化为心肌细胞的能力，胚胎干细胞或胚胎干细胞来源的细胞的移植仍面临着一些非常棘手的问题：（1）移植物排斥反应，通过药物诱导免疫抑制本身就是一种疾病；（2）心律失常，研究发现在灵长类动物中移植人类胚胎干细胞来源的细胞会导致危及生命的心律失常，而这种心律失常的发生与剂量无关；（3）恶性肿瘤，在当代临床研究中，对恶性肿瘤等灾难性影响的耐受限度为零。尽管胚胎干细胞分化成肿瘤的可能性非常低，但不是完全没有可能，特别是移植细胞的数量级在十亿的时候；（4）长期再生能力，虽然胚胎干细胞和胚胎干细胞来源的细胞被吹捧为具有长期再生能力，但干细胞示踪技术显示这些细胞在移植后迅速消失，没有长期移植或再生的证据；（5）越来越多的证据表明胚胎干细胞的作用是通过旁分泌机制来发挥的，尚没有开展或启动胚胎干细胞来源细胞在心血管疾病中的临床对照试验；作者最后对未来发展的方向做了预估：（1）成年细胞已用于数千名心脏病患者，没有显著的副作用，其结果令人鼓舞，值得进行II期和III期试验。（2）人诱导的多潜能干细胞提供类似胚胎干细胞的多能性，而不需要终身免疫抑制。《COVID-19患者中使用秋水仙碱治疗对心脏、炎症指标及临床预后的影响》JAMA Network Open，2020年6月 (11)研究旨在比较秋水仙碱和标准化治疗对心脏、炎症指标及临床预后的影响。在105例随机临床试验中，秋水仙碱干预组在常规治疗的基础上，首剂1.5mg，如果没有观察到胃肠道不良反应则60分钟后再给0.5mg，维持剂量为0.5mg qd（体重60kg）直至出院或满21天。对照组的主要临床终点、临床恶化率高于秋水仙碱组，而且对照组患者出现恶化比较快。两组高敏肌钙蛋白浓度无差异，但秋水仙碱组患者D-二聚体的增幅较小。结论：秋水仙碱对COVID-19由一定的治疗作用。参考文献1.Khanna A, Ostermann M, Bellomo R. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017;377(26):2604.2.Bellomo R, Forni LG, Busse LW, McCurdy MT, Ham KR, Boldt DW, et al. Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial. Am J Respir Crit Care Med. 2020;202(9):1253-61.3.Silvain J, Kerneis M, Zeitouni M, Lattuca B, Galier S, Brugier D, et al. Interleukin-1beta and Risk of Premature Death in Patients With Myocardial Infarction. J Am Coll Cardiol. 2020;76(15):1763-73.4.Everett BM, MacFadyen JG, Thuren T, Libby P, Glynn RJ, Ridker PM. Inhibition of Interleukin-1beta and Reduction in Atherothrombotic Cardiovascular Events in the CANTOS Trial. J Am Coll Cardiol. 2020;76(14):1660-70.5.Rothman AM, MacFadyen J, Thuren T, Webb A, Harrison DG, Guzik TJ, et al. Effects of Interleukin-1beta Inhibition on Blood Pressure, Incident Hypertension, and Residual Inflammatory Risk: A Secondary Analysis of CANTOS. Hypertension. 2020;75(2):477-82.6.Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019;381(26):2497-505.7.Bouabdallaoui N, Tardif JC, Waters DD, Pinto FJ, Maggioni AP, Diaz R, et al. Time-to-treatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT). Eur Heart J. 2020.8.Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, et al. Colchicine in Patients with Chronic Coronary Disease. New England Journal of Medicine. 2020.9.He L, Nguyen NB, Ardehali R, Zhou B. Heart Regeneration by Endogenous Stem Cells and Cardiomyocyte Proliferation. Circulation. 2020;142(3):275-91.10.Wysoczynski M, Bolli R. A realistic appraisal of the use of embryonic stem cell-based therapies for cardiac repair. Eur Heart J. 2020;41(25):2397-404.11.Deftereos SG, Giannopoulos G, Vrachatis DA, Siasos GD, Giotaki SG, Gargalianos P, et al. Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial. JAMA Network Open. 2020;3(6):e2013136-e.

In Part 2 of this "Mini Grand Rounds" series, we discuss important side effects of ATII including thrombosis, especially in the setting of COVID. References:Celi A, Cianchetti S, Dell'Omo G, Pedrinelli R. Angiotensin II, tissue factor and the thrombotic paradox of hypertension. Expert Review Cardiovasc Therapy. 2010. 8 (12)Senchenkova EY, Russell J, Almeida-Paula LD, et al. Angiotensin II-mediated microvascular thrombosis. Hypertension. 2010; 56 (6): 1089-1095Zhang P, Zhu L, Cai J, et al. Association of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res. 2020: 126 (12): 1671-1681Tralhao A, Moita LF, Povoa P. Potential benefits of angiotensin II in COVID-19 patients: beyond reasonable doubt? Crit Care. 2020; 243 (324)Zangrillo A, Landoni G, Beretta L, et al. Angiotensin II infusion in COVID-19-associated vasodilatory shock: a case series. Crit Care. 2020; 24: 227Want H, Das S, Wieruszewski PM, et al. Unexpected BP sensitivity to angiotensin II in a patient with coronavirus disease 19, ARDS, and septic shock. CHEST. 2020; 158 (2): e55-58

In Part 1 of this "Mini Grand Rounds" series, we discuss Angiotensin II use for vasodilatory shock, reviewing the ATHOS-3 trial and real-world experiences. References:Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. NEJM. 2017; 377: 419-430Farina N, Bixby A, Alaniz C. Angiotensin II brings more questions than answers. P T. 2019; 43 (11): 685- 687

Le Professeur Jean-Louis Vincent, qui est PUPH dans le service de MIR du CHU Erasme à Bruxelles, nous parle des vasopresseurs dans le choc septique. Aucun lien d’intérêt déclaré. Sommaire : Quels vasopresseurs utiliser ?Quel(s) est/sont son/ses mécanismes d’actions ?Quand le débuter, avec quelle cible et quand l’arrêter ?Quel est le vasopresseur d’avenir ? Références : Vincent J-L, De Backer D. Circulatory shock. N Engl J Med. 31 oct 2013;369(18):1726‑34.De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, et al. Comparison of Dopamine and Norepinephrine in the Treatment of Shock. N Engl J Med. 4 mars 2010;362(9):779‑89.Sun Q, Dimopoulos G, Nguyen DN, Tu Z, Nagy N, Hoang AD, et al. Low-dose vasopressin in the treatment of septic shock in sheep. Am J Respir Crit Care Med. 15 août 2003;168(4):481‑6.Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 03 2017;377(5):419‑30.Bai X, Yu W, Ji W, Lin Z, Tan S, Duan K, et al. Early versus delayed administration of norepinephrine in patients with septic shock. Crit Care Lond Engl. 3 oct 2014;18(5):532.

In this episode of Critical Matters, we will discuss hypotension and new data on Angiotensin II within the context of our path towards personalized vasopressor support. Our guest is Dr. Ashish K. Khanna. Dr. Khanna is an anesthesia and critical care practicing physician. He is Associate Professor, and Section Head for Research, in the Department of Anesthesiology, Section on Critical Care Medicine of the Wake Forest School of Medicine, in Winston-Salem, North Carolina. He is a prolific author and researcher and was the lead author of the ATHOS-3 study in the New England Journal of Medicine. The results of which led to the approval of Angiotensin II as a vasopressor for the treatment of refractory hypotension in adults with septic or other types of distributive shock. Links: The Relationship Between ICU Hypotension and In-Hospital Mortality and Morbidity in Septic Patients: https://bit.ly/2D1epJQ Association between Mean Arterial Pressure and Acute Kidney Injury and a Composite of Myocardial Injury and Mortality in Postoperative Critically Ill Patients: A Retrospective Cohort Analysis: https://bit.ly/2QuyStz Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3 Trial): https://bit.ly/2G27hhB Survival After Shock Requiring High-Dose Vasopressor Therapy: https://bit.ly/2EkLm4P Renin as a Marker of Tissue-Perfusion and Prognosis in Critically Ill Patients: https://bit.ly/3jiKT1L Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock: https://bit.ly/2G1tZGB Additional Content Related to Angiotensin II: Angiotensin II for Vasodilatory Shock: 2019 Update: https://bit.ly/3hvVkyA Personalization of Vasopressor Therapy in the Treatment of Vasodilatory Shock: https://bit.ly/3hy7wyD

When should you pull the trigger on Angiotensin II for vasodilatory shock?

This month on Episode 13 of the Discover CircRes podcast, host Cindy St. Hilaire highlights three featured articles from the June 5 issue of Circulation Research and gives listeners an inside scoop on the cutting-edge ideas in the June 19th Compendium on Atrial Fibrillation. This episode also features an in-depth conversation with Dr David McManus on emerging technologies for identifying AFib.    Article highlights:   Zhang, et al. ACEI/ARB on COVID-19 in patients with hypertension Sakamoto, et al. ERR Signaling and Cardiac Maturation Xie, et al. CIRP Governs the Heart Rate Response to Stress Cindy St. Hilaire:           Hello and welcome to Discover CircRes, the podcast for 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. Today, I'm going to share with you three articles selected from the June 5th issue of Circulation Research as well as give you an overview of the Compendium on Atrial Fibrillation also coming out in June. We'll follow that by having a discussion with Dr David McManus regarding his review on the emerging technologies for identifying AFib in the general population. So first, the highlights. The first article I'm sharing with you is titled Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients with Hypertension Hospitalized with COVID-19. The first author is Peng Zhang and the corresponding author is Hongliang Li and they're from Wuhan University in Wuhan, China. Patients with hypertension have increased risk of death from COVID-19. While the high blood pressure itself is likely to contribute to this, concerns have been raised that medications used to treat hypertension, specifically ACE inhibitors and Angiotensin II receptor blockers may worsen coronavirus infection. Research in animals showed that these drugs increased expression of ACE-2, the protein on lung epithelial cells that is used by the virus to gain entry into the host cell where it can then replicate. However, other conflicting evidence has shown that these drugs might reduce lung injury in pneumonia patients, which is also a complication of COVID. To weigh up the benefits and risks of ACE inhibitors and Angiotensin II receptor blockers, Zhang and colleagues performed a retrospective analysis of 1,128 patients with COVID-19 and hypertension who are treated at nine hospitals in Hubei Province, China. Of the patients, 188 took the hypertensive medicine during their hospital stay and 940 did not. The ages, sexes and comorbidities of the two groups were very similar. After 28 days of follow up, 99 of the patients had died, seven from the group taking the hypertensive medications, equivalent to 3.7% and 92 from the group that did not or 9.8%. The team concludes that treatment of hypertension patients with hypertension medications does not increase risk of COVID-19 mortality and may even reduce the threat. However, a much larger sample size would be necessary to fully confirm. The second article I want to highlight is titled A Critical Role For Estrogen Related Receptor Signaling and Cardiac Maturation. The first authors are Tomoya Sakamoto and Timothy Matsuura and the corresponding author is Daniel Kelly from the University of Pennsylvania.  From fetal to postnatal development, the human heart goes through significant changes, including the expansion of mitochondrial numbers, a change in fuel utilization within the mitochondria and replacement of fetal contractile proteins for the adult ones. Further, there is increases in ion uptake and release. Transcription factor estrogen-related receptor was known to drive postnatal mitochondrial biogenesis and now this group has shown that it also drives these developmental changes. They developed a genetic model to knock down expression of estrogen-related receptor in early postnatal mice. When the animals were five weeks old, they performed transcriptomic analysis. In mice lacking estrogen-related receptor, there was a reduction in expression of genes involved in ion channeling in handling, fatty acid oxidation, which is the major metabolic process in the adult heart, as well as adult versions of the contractile proteins. By contrast, expression of genes and coding field contractile proteins and factors, specifically those involved in glycolysis, was upregulated. In heart failure, cardiomyocytes can revert to fetal-like cells. The authors, therefore, suggest that boosting estrogen-related receptor might be a way to counteract such pathology as well as a way to induce and study cardiomyocyte maturation and cultured progenitor cells. The next article I want to share with you is titled Cold-Inducible RNA-Binding Protein Prevents the Excessive Heart Rate Response to Stress by Targeting Phosphodiesterase. The first authors are Duanyang Xie and Li Geng and the corresponding author is Yi-Han Chen and they're from the China Ministry of Education. During a fight-or-flight situation, also known as the acute stress response, the heart rate increases rapidly due to the effects of adrenergic signaling on the cells in the sinoatrial node, which is the heart's pacemaker. Within sinoatrial node cells, levels of the signaling factor, cyclic AMP, ramp up and this, in turn, increases the cell's calcium handling and contraction rate, but excessive or prolonged racing heartbeat can be damaging and it is unclear what keeps the system in check. This group has now shown that cold-induced RNA-binding protein or CIRP puts the brakes on the heart by regulating cyclic AMP levels. The team showed that while baseline rates between wild-type and CIRP-deficient rats were the same, triggering the adrenergic signaling via treatment with isoproterenol caused CRP-deficient rat hearts to beat faster for longer than in the wild-type counterparts. Cardiac tissue from the CIRP-lacking rats showed higher than usual levels of cyclic AMP after isoproterenol treatment. This was due to lower than usual levels of phosphodiesterase, the enzyme that normally degrades cyclical AMP. The team went on to show that CIRP normally binds and stabilizes phosphodiesterase's messenger RNA and sharing a ready supply of the enzyme to restrain cyclic AMP signaling. As well as revealing this crucial control mechanism, the work highlights CIRP as a potential new target for future heart rate lowering medications. The last thing I want to share with you before we switch to our interview is our Atrial Fibrillation Compendium. Atrial fibrillation, or AFib, is a major cause of morbidity and mortality globally. There have been significant advances in the detection, management and treatment of AFib over the past two decades. However, the burden of the disease continues to increase. This Compendium on AFib features articles on epigenetics and transcriptional networks underlying atrial fibrillation, inflammasomes and proteostasis, novel molecular mechanisms associated with atrial fibrillation, emerging technologies with the identification of atrial fibrillation, epidemiology of atrial fibrillation in the 21st century, how will genetics inform the critical care of AFib, how will machine learning inform the clinical care of AFib, population-based screening for AFib, the molecular basis of AFib pathophysiology and therapy, the genetics of AFib in 2020, GWAS genome sequencing, polygenetic risk and beyond, is there hope for animal models of AFib and ablating AFib in 30 minutes, new technologies for safer and more efficient pulmonary vein isolation. Okay. So we're now going to switch over to the interview portion of the podcast. I have with me, Dr David McManus, who is a professor of medicine in the Division of Cardiology and the Department of Medicine at UMass Medical Center in Worcester, Mass and he's also a cardiac electrophysiologist. And today, we're going to be discussing his recent Review on the emerging technologies for identifying atrial fibrillation, also known AFib, So thank you so much for taking the time to speak with me today. David McManus: My pleasure. Thanks for inviting me. Cindy St. Hilaire: Yeah, so before we dig into the review and about the emerging technologies for AFib, can you maybe give me a brief explanation of what is AFib, who gets it and what's the spectrum of disease severity in the patients that do get AFib? David McManus: Sure, so atrial fibrillation is the world's most common sustained heart rhythm problem. It is associated with a number of different health conditions in terms of risk factors. The biggest risk factor for getting this rhythm problem is age, so it's most common in people over the age of 40 and it increases ... in fact, it doubles in terms of the incidents with each decade of life. So as you get into your 80s and 90, it's really quite common. The additional risk factors are kind of common things that you might imagine and a few things you might not, things like diabetes and high blood pressure that are also risk factors forgetting plaque in your heart arteries are also risk factors for AFib, but some other risk factors that are a little more controversial with respect to heart artery disease, things like alcohol consumption, even if it's red wine, which otherwise might seem to have some benefit, is actually a risk factor too for AFib. In fact, in the old days, some doctors used to refer to AFib as holiday heart because of its association with acute alcohol intake around the holidays. So, the fact is that AFib is related to some health behaviors like drinking. It's also related to a condition called sleep apnea or sleep-disordered breathing. Weight is associated with getting AFib. So all these things combined with your genetics, your family history and your age to contribute to getting this disease, so those are the most common risk factors. The question about why it is important to diagnose? It was a disease that people sort of treated like gray hair for a long time. Something that you might not want to have, but is not particularly impactful, but some really important studies, especially in the 70s and 80s, started to establish a link between atrial fibrillation and clot-based strokes and so that is a very strong relationship that exists between people who get AFib and a much higher risk of having a clot form in the heart and traveling to the brain. Cindy St. Hilaire: Which is obviously very dangerous. So how often does AFib go undetected? Because I think that's kind of at the core of using this new technology. Once you get AFib, do you know you have it right away? David McManus: So, that's exactly right. The fact is that we don't truly know, right? Because by definition it's undiagnosed. We don't really know how long your average person goes before they're diagnosed and I think it varies a lot, but it's important to know a couple of things about AFib to sort of talk around the perimeter of this answer and try to kind of hone in a bit.  So first off, some people who develop AFib don't feel it or they have very minimal symptoms or they have symptoms that come and go so quickly. By the time they get in for an evaluation, the arrhythmia is gone so it can be what's called paroxysmal in its early stages, which means it can come and go. The duration of that AFib can be minutes or hours or even in some cases, seconds, and therefore elude a diagnosis. The other thing is symptoms from AFib, when they do exist, are not always the sensation of palpitation, a sensation of an irregularity. Some people just feel short of breath when they go up a flight of stairs and- Cindy St. Hilaire: Which you can associate with age. David McManus:  ... they may attribute that symptom to being older. Yeah. Right. They may just think "I'm getting tired because I'm older," or "I'm out of shape." And so the simple answer is, I guess, I'd start with this statistic. A significant minority of patients with atrial fibrillation present with a stroke as their first clear manifestations, so they come in with stroke. The estimates on that vary considerably, but at least one in five patients who present with a stroke have a first diagnosis of AFib at the time of that stroke and about 5% of patients with AFib overall present with stroke as their first manifestation. Those are two different statistics to kind of come at it different ways and that's what you're trying to prevent. You want to make the diagnosis of AFib before the stroke because we have a lot of really good treatments that can prevent stroke if you know you have it. Cindy St. Hilaire: Right and so I think that gets to this idea of maybe screening patients of a certain age. I don't know what that age cutoff would be. But when you look at the guidelines right now, there is no clear guideline. The US Preventative Task Force says there's no good data to screen patients beforehand. I think the AHA and the ACC just don't have any guidelines regarding screening. But yet in Europe and Australia, they do perform opportunistic screening for AFib patients and this is in the clinic. This is now with ECGs. They screen for patients over 65. So based on this statistic you said that 20% of stroke patients had undetected AFib, why is there not a specific guideline? Where does that come from? David McManus: I think you're spot on that there's a lot of controversy about this right now and that's good because the reason I think it's controversial is there's some emerging technologies and opportunities that didn't exist before. Because pretty clearly, before doing a conventional 12-lead EKG in the office, did not offer sufficient benefit over and above usual care to demonstrate to groups like the US Preventative Service Task Force, which issues the guidance around things like breast cancer screening and colon cancer screening, so they have to weigh costs, financial costs, harms from false-positive tests. And so, the reason there's controversy is because what we had previously was a pretty suboptimal situation for screening. We had intermittent tests, which were of significant costs and they were spaced so far apart and required coming in for clinical care that there was really no benefit to doing them over and above taking someone's pulse in the office. But there's no question that there are groups. There's a group called the AF-SCREEN Group, for example, that is really challenging the research community and clinicians to revisit some of these assumptions about screening, given new technologies and how we might thoughtfully use them in a pharmacy, for example, or in a clinic or at home with commercial technologies to study that. Because, really, to make a recommendation that screening is clearly beneficial, you have to do some kind of a study or studies that show that not only can you diagnose more of the arrhythmia, but that by diagnosing it, you can do something about it and that that action, in this case, anticoagulation, leads to a reduction in stroke and without a significant increase in harm from that treatment and that's somewhat controversial because this is a disease…the technologies that we have now are creating new diseases, right? So in a sense, we've created the new disease, undiagnosed AFib. And so, okay, we found it. Now, is it kind of like cancer where finding it earlier maybe has a different prognosis than finding it later in terms of risk? Some people think so. And in that case, you really have to prove that finding it early and treating that early form with the treatment that you have for the late form works as well and doesn't cause harm. So that's kind of where we are right now is there a number of really big studies going on that are hoping to help inform this more, which is pretty cool. Cindy St. Hilaire: Yeah. And so on that note, my parents got new supplemental insurance. They're both retired and this new insurance came with a nurse that dropped by your house and just kind of did a wellness check. And that nurse came and checked my mom's pulse, asked her how she was feeling and checked it again and said, "You're going to your doctor. You're in AFib," and she had no symptoms of that. She's 69, she's very healthy, she's active. And essentially in the course of a couple of months, she went from what she thought was normal to not being able to take one step up one stair because her AFib got so bad and she obviously saw a cardiologist and they got her on blood thinners. And eventually, after two cardioversions, things stuck and it's now in control, but one of the things that we did was we immediately bought her an at-home KardiaMobile heart monitor. That is essentially what you're reviewing now and I'm wondering if you could maybe give us a little bit of information about this. So, there's multiple devices out there. There's the KardiaMobile. There's also the Apple Watch and the Fitbit that are starting to get these kinds of technologies. And so for us, it was at least reassuring to see her heart rate was something and now it's getting more normal with the medicine. And now even after the cardioversion, it's been a couple of months, she checks it once a day to make sure it's still functioning as it should. So can you tell us a little bit about these and about what this might mean for the future of AFib and clinical management? David McManus: Sure. So you are using an FDA-cleared technology. You've referenced the AliveCor KardiaMobile. It's in a recent survey that the Heart Rhythm Society did. One of the most common ones that's purchased or advised to patients to buy by their cardiologists and healthcare providers and I think it was cleared about 2015. And what it is is it's a credit card-sized device that gets you a 1-lead EKG and it records about 30 seconds. And then that data, it can be transmitted directly to your cardiologist. Cindy St. Hilaire: She actually would bring her phone in and show them, "Look at my last week." David McManus: Yeah, you can do it that way or, like many of my patients are, just constantly emailing them or putting them in their electronic health record, which speaks to a whole other ball of wax. But that is a very valuable tool for people who are at risk for AFib or know they have it and want to monitor themselves for things like recurrences, to check their rhythm, check their rate, so that's an FDA-cleared device. And it also provides an automated read so that she is able to see at the top of the EKG what the computer thinks her heart rhythm is and that is a really nice technology that's been fairly well studied in a variety of different settings, including people like your mom who have had a prior cardioversion, to look for recurrences. So that's one approach that exists, which is for intermittent monitoring. And that's also in essence, the same approach that one of the two tools that an Apple Watch has embedded in it. So the Apple Watch 4 and 5 are also FDA-cleared for similar analysis. So the Apple Watch has a EKG on the bevel of the watch. The thing you turn to change the time, not really in an Apple Watch, but in an old-fashioned watch. And so you can kind of put your finger on it and again, create that same circuit in your body to record a single-lead EKG and that similarly can present a 30-second EKG strip, so it's very similar to what AliveCor's KardioMobile does. Just in the watch. But again, that's an EKG-based approach and those approaches are not the only technologies that are out there. There are a number of other devices that have CE marking designation in Europe. Other devices that are starting to become available in the US and we go through some of the performance of those devices in our review. And generally speaking, the ECG approach, the advantage is it's one of the more accurate approaches to AFib detection, but it does require, at least right now, that you intermittently check yourself.  In contrast, there's a movement afoot, and Apple has a separate  FDA clearance, to use the lens and video camera on the back of the watch, that was previously used to measure your heart rate, to analyze the skin color changes that happen when your blood is flowing in and out of your wrist, to your hand. It looks at that skin color change, records it and analyzes it for irregularity. So it's an essence, like someone checking your pulse and it's called pulse plethysmography and that recording is similar to what other groups are analyzing. For example, there's something called FibriCheck, which is an app that is FDA cleared for AFib detection. But again, you put your finger on the camera of your iPhone or Android and it analyzes the pulse. Cindy St. Hilaire: So a patient has to actively say, "I'm going to check this right now," as opposed to a background assessment? David McManus: Yeah, so just to be clear. The background assessment is the automated sort of pulse check that the Apple Watch is doing and then it can prompt you to perform your own EKG, so that's the difference between kind of an intermittent-check approach versus a more near-continuous ... it's not truly continuous, but it's a near-continuous approach Cindy St. Hilaire: So are there any drawbacks to people more regularly performing these in their kitchen? As a clinician, what are the drawbacks? David McManus: It really is exciting and I think there are a lot of good reasons to pursue this. As you know, I'm sort of an early adopter of this idea and so I definitely would side with you that I think there were a lot of good reasons to be using these technologies. I just want to highlight though that there are a couple of issues. So when commercial technology companies build medical-grade tech intended to diagnose or detect rhythm problems, those rhythm problems come to the clinics in a very different way and from a different type of patient, so they're not necessarily contextualized the same way a workup would happen if you came into the doctor, they prescribed a medical-grade patch monitor or a traditional monitor or did another type of medical test on you. You're kind of on your own. And so when you get the diagnosis or you get the possible diagnosis, you have very little information,  and it can be anxiety-provoking. In many cases, especially in younger people ... in fact, the majority of people who have Apple Watches are at really low risk from having a complication from AFib. So now, you're making an upstream diagnosis and you may not do anything about it other than introduce a word onto their chart. And so, yeah, I do think there's some things that warrant further study and evaluation about some of the unintended downstream consequences of making diagnoses earlier and worrying people about a condition. David McManus: Now, some have argued that an early diagnosis, even if you wouldn't put someone on a blood thinner, as you call it or an anticoagulant ... Like for example, maybe you change your health behaviors, maybe you lose some weight or you get more active or you stopped drinking so much. So I happen to think that early diagnosis is a good thing, but I do think that we don't really have robust care-management systems across the country that can support people who are at home. It's really hard right now for your doctor to, on top of seeing 30 patients in the office, to find the time to respond to your new test that he didn't order or she didn't order. Cindy St. Hilaire: I got this blip on my strips. David McManus: Yeah, what do I do about this? Well, okay, now I got to see you, what tests are ordered, what's the process and I think there's a lot of opportunity for us to, especially in the COVID era, redesign how we're delivering heart care and integrating these technologies become a facilitator as opposed to a burden, so I think there's a lot of interest in incorporating them. But right now, at least, they're kind of separate from your chart, in the electronic chart and your doctor has to sort of find a way of reviewing on your smartphone, in the office, finding extra time to do that. They're not really paid to do that, how do you protect the safety of that information and et cetera, et cetera. So there are all these sort of little, but they seem little, but they're actually kind of important downstream implications. So we talk a little bit about, and this is kind of a unique part of this Review, the clinical actionability of device-detected AFib. There's no debating the fact that AFib is bad, but the real impact of device-detected AFib remained something that we really need to define and so there's a lot of interesting work going on in this area. Cindy St. Hilaire: And so, because we're still all at home because of the COVID epidemic, there's been some things in the news regarding some of these wearable technologies being able to detect or track trends in swaths of patient health. Where do you see this going in terms of either things like COVID and epidemics or even things regarding AFib and we always see those maps from the AHA with hotspots of diabetes, things like that, so how do you think that this kind of technology can help transition the future of medical care, specifically in the US? David McManus: I think it's really exciting because everybody has a smartphone and that crosses age, sex, race, occupation, religion and I think people are increasingly understanding the connections between health behaviors and their heart health. And I think, for example, just using your heat map example, that there's a stroke belt and a diabetes belt and different areas in the United States, also tremendous rural health disparities, that mobile devices have a really remarkable opportunity to help us understand what is going on, what is driving these sort of risks? Is it stress, is it alcohol, food consumption, nutrition, activity, sleep, all the things we talked about? And whether it be AFib or other cardiovascular conditions, these wearable devices and mobile devices and digital technologies allow for quantifying different health behaviors and mood and opinion and activity in ways that our  regular in-person exams that we do, when we see you for an hour or two every 365 days, we just really don't quantify. And I look forward to a time in the near future where your vital signs that are presented for your visit with your doctor over the internet is your activity, your blood pressure from your watch or heart rate from your watch or EKG, your oxygen levels at any of a myriad of other things that these devices can impact or will in the near future. Cindy St. Hilaire: Yeah, I agree. I think it's great. And I think also it helps to empower the patient. David McManus: Oh, for sure. I mean, if done well, it really connects you as a patient to your health more and it also, if done well, could connect you better to your healthcare team. I mean, a lot of people are afraid in the healthcare community of this technology replacing them, but that only will happen if we don't incorporate it as a tool into our relationships with our patients. I think if it's done in that way, it's a facilitator. It actually makes your mom maybe feel more connected to her cardiologist to be able to kind of run that list. Cindy St. Hilaire: Yeah and she understands what she's looking at more, so it's been wonderful. Well, thank you so much. This was an excellent Review; it was really timely and thank you again for the contribution and for taking the time to speak with me today. David McManus: My pleasure and thanks for the invitation and I hope people will read the Review. Cindy St. Hilaire: Great. Wonderful. Well, thank you so much, David. David McManus: Good luck to you and your mom. Cindy St. Hilaire: So that's it for the highlights from our June issues of Circulation Research and our compendium on atrial fibrillation. Thank you for listening. Please check out the Circulation Research Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, Dr David McManus. This podcast is produced by Rebecca McTavish and Ishara Ratnayaka, edited by Melissa Stoner and supported by the editorial team of Circulation Research. Some of the copy text for highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire And this is Discover CircRes, you're on-the-go source for the most up-to-date and exciting discoveries in basic cardiovascular research.  

Dr. Chastity Bradford completed her undergraduate studies at Spelman College (an HBCU) earning a B.S. in Biology. While there she was a Microbiology Scholar, received a Howard Hughes Fellowship (Loyola University, Chicago, IL), and made Spelman College's Honor Society as well as the Dean's List. Chastity started her graduate studies in the Department of Cellular and Molecular Physiology at the University of Alabama at Birmingham (UAB). Her research area focused on Cardiovascular Physiology in Dr. Pamela A. Lucchesi's Lab. Her dissertation work focused on The Role of the Renin-Angiotensin System in Extracellular Matrix Remodeling During the Progression of Hypertension and the Development of Cardiac Fibrosis Currently, Dr. Bradford is an Associate Professor of Biology in the College of Arts and Science at Tuskegee University (an HBCU). As the Principal Investigator of her own lab, the Bradford Lab, she uses hemodynamic, molecular, biochemical, and immunohistological analyses to determine if ACE2 overexpression prevents Angiotensin-II induced HTN and rescues Pulmonary Hypertension. --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app

Dr. Michael McCurdy presents Pulmonary Grand Rounds. The title of his talk is "Angiotensin II for vasodilatory shock in the era of COVID-19"

In today's VETgirl online veterinary continuing education podcast, we review the use of telmisartan for the treatment of systemic hypertension in cats. Systemic hypertension (SH) in aged cats is predominantly due to chronic kidney disease (CKD), hyperthyroidism, or considered idiopathic. Downstream end-organ effects of chronic systemic hypertension target the eyes, myocardium, central nervous system, and kidneys (specifically, worsened renal function and proteinuria). Activation of the renin-angiotensin-aldosterone (RAAS) system contributes to development of SH in many cases and drugs that inhibit this system have treatment potential. Angiotensin II receptor blockers (ARBs) specifically block the angiotensin II, subtype-1 receptor (AT1) therefore inhibiting angiotensin II, which causes vasoconstriction, volume retention, sympathetic stimulation, inflammation, and fibrosis.

In today's VETgirl online veterinary continuing education podcast, we review the use of telmisartan for the treatment of systemic hypertension in cats. Systemic hypertension (SH) in aged cats is predominantly due to chronic kidney disease (CKD), hyperthyroidism, or considered idiopathic. Downstream end-organ effects of chronic systemic hypertension target the eyes, myocardium, central nervous system, and kidneys (specifically, worsened renal function and proteinuria). Activation of the renin-angiotensin-aldosterone (RAAS) system contributes to development of SH in many cases and drugs that inhibit this system have treatment potential. Angiotensin II receptor blockers (ARBs) specifically block the angiotensin II, subtype-1 receptor (AT1) therefore inhibiting angiotensin II, which causes vasoconstriction, volume retention, sympathetic stimulation, inflammation, and fibrosis.

Vasoactives in Septic Shock with Special Guest: Alex Flannery, PharmD, BCCCP, BCPS3:35 – Why is Alex interested in sepsis?...5:49 – How do you teach sepsis with the recent changes?...8:35 – When to start vasopressors in a hypotensive patient?...11:58 – What do you consider high-dose norepinephrine?...13:40 – How do you add vasopressin and corticosteroids for patients in refractory septic shock?...15:15 – Do you use fludricortisone in combination with hydrocortisone?...16:49 – Utility of cortisol levels or ACTH stimulation testing...18:27 – Cost:benefit analysis of vasopressin...19:21 – Role of epinephrine in septic shock...21:15 – Dobutamine or Epinephrine?...22:57 – HAT cocktail...24:55 – Thiamine supplementation in sepsis and septic shock...28:35 – Use of Angiotensin II and its place in therapy...32:30 – Approach to using methylene blue...34:05 – Modify hemodynamic goals to assist with vasopressor weaning...36:07 – Managing adverse effects due to vasopressors...39:27 – Order of operations in weaning vasopressors and corticosteroids...44:35 – The use of midodrine to wean off IV vasopressors...49:25 – Take-away points for vasoactives and their use in septic shock...51:11– Future areas for research PharmacyToDose.Com@PharmacyToDose on Twitter/InstragramPharmacyToDose@Gmail.com

  Episode 278 is an all inclusive guide to kidney anatomy, health, bloodwork, and MORE for physique and performance based athletes! First I dig into some basics on kidney anatomy and function before moving into some considerations for athletes looking to get bloodwork done to track kidney health, and all before ending with practical application on how to maintain kidney health while pushing for your goals! Also, theres a few references I'll provide below for those looking to take things further!   REFERENCES Adelstein RS, Sellers JR. Effects of calcium on vascular smooth muscle contraction. The American journal of cardiology. Jan 30 1987;59(3):4b-10b.   Agre P, King LS, Yasui M, Guggino WB, Ottersen OP, Fujiyoshi Y, . . . Nielsen S. Aquaporin water channels--from atomic structure to clinical medicine. The Journal of physiology. Jul 1 2002;542(Pt 1):3-16.   AHA. American Heart Association. Kidney Damage and High Blood Pressure. Available at: http://www.heart.org/HEARTORG/Conditions/HighBloodPressure/WhyBloodPressureMatters/Kidney-Damage-and-High-Blood-Pressure_UCM_301825_Article.jsp. Last updated 9/11/2014a. Accessed 8/10/2014.     Akinwusi PO, Oluyombo R, Ogunro PS, Adeniji AO, Okunola OO, Ayodele OE. Low dose aspirin therapy and renal function in elderly patients. International journal of general medicine. 2013;6:19-24.   Al-Awqati Q, Barasch J, Goldman L (ed.), SchaferAI (ed.). Goldman's Cecil Medicine, Twenty-Fourth Edition. Chapter 117: Structure and Function of the Kidneys; 716-720. Copyright 2012 Saunders, an imprint of Elsevier, Inc. Available at: www.clinicalkey.com Accessed: 6/9/2014.   Alpern RJ, Sakhaee K. The clinical spectrum of chronic metabolic acidosis: homeostatic mechanisms produce significant morbidity. American journal of kidney diseases : the official journal of the National Kidney Foundation. Feb 1997;29(2):291-302.   Amodu A, Abramowitz MK. Dietary acid, age, and serum bicarbonate levels among adults in the United States. Clinical journal of the American Society of Nephrology : CJASN. Dec 2013;8(12):2034-2042.   Anders HJ, Andersen K, Stecher B. The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease. Kidney international. Jun 2013;83(6):1010-1016.   Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, and Thornalley PJ. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes. 2003;52(8):2110–20   Bae EH, Lee J, Ma SK, et al. alpha-Lipoic acid prevents cisplatin-induced acute kidney injury in rats. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 2009;24(9):2692–700   Balakumar P, Bishnoi HK, Mahadevan N. Telmisartan in the management of diabetic nephropathy: a contemporary view. Current diabetes reviews. May 2012;8(3):183-190.   Balakumar P, Rohilla A, Krishan P, Solairaj P, and Thangathirupathi A. The multifaceted therapeutic potential of benfotiamine. Pharmacol. Res. 2010;61(6):482–8   Bankir L, Bouby N, Trinh-Trang-Tan MM, Ahloulay M, Promeneur D. Direct and indirect cost of urea excretion. Kidney international. Jun 1996;49(6):1598-1607.   Barbagallo M, Dominguez LJ, Galioto A, Pineo A, Belvedere M. Oral magnesium supplementation improves vascular function in elderly diabetic patients. Magnesium research : official organ of the International Society for the Development of Research on Magnesium. Sep 2010;23(3):131-137.   Bashir B, Sharma SG, Stein HD, Sirota RA, D'Agati VD. Acute kidney injury secondary to exposure to insecticides used for bedbug (Cimex lectularis) control. American journal of kidney diseases : the official journal of the National Kidney Foundation. Nov 2013;62(5):974-977.   Baynes JW, Dominiczak MH. Medical Biochemistry, Fourth Edition. 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In this episode of Critical Matters, listen to the recording of Sound Critical Care’s webinar, Personalized Selection of Vasopressors in the Treatment of Shock. Our guest for this episode is Dr. Lakhmir Chawla, Chief Medical Officer of La Jolla Pharmaceutical in San Diego, California. During this webinar, we discuss lessons learned from the clinical use of the new vasopressor Angiotensin II, as well as personalization of vasopressor therapy in the treatment of vasodilatory shock. Watch the video recording: https://bit.ly/2jZ1z5h

In this episode of Critical Matters, we discuss lessons learned from the clinical use of Angiotensin II (GIAPREZA™), which was approved for use in patients with vasodilatory shock a little over a year ago. Our guest is Dr. Lakhmir S. Chawla, Chief Medical Officer of La Jolla Pharmaceutical in San Diego, California. Dr. Chawla was the designer and lead investigator of the ATHOS (Angiotensin II for the Treatment of High Output Shock) trial which results led to the ATHOS 3 trial, (The Phase 3 clinical trial of angiotensin II, for the treatment of catecholamine-resistant hypotension). ADDITIONAL RESOURCES: ATHOS-3 Clinical Trial. Randomized controlled trial evaluating the efficacy of Angiotensin II in raising blood pressure in vasodilatory shock: https://bit.ly/2r5SpG0 Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II: https://bit.ly/2JttWTj Sensitivity to angiotensin II dose in patients with vasodilatory shock: a prespecified analysis of the ATHOS-3 trial: https://bit.ly/2xDVVsr ALBUMS AND BOOKS MENTIONED IN THIS EPISODE: The Dark Side of the Moon, Pink Floyd: https://amzn.to/2XZr34x Wish You Were Here, Pink Floyd: https://amzn.to/2Lc2lbb Loonshots: How to Nurture the Crazy Ideas That Win Wars, Cure Diseases, and Transform Industries, Safi Bachall: https://amzn.to/2S4IrPU

In our first episode of the Critical Matters podcast, we discussed the potential role of Angiotensin II in the treatment of distributive shock based on the results of the ATHOS 3 clinical trial. Now Angiotensin II is FDA approved and commercially available as a product named GIAPREZA™. In this episode we will discuss this topic further. Our guest is Dr. Lakhmir S. Chawla, Chief Medical Officer of La Jolla Pharmaceutical in San Diego, California. Previously, Dr. Chawla was a Professor of Medicine at the George Washington University. During his tenure at George Washington, Dr. Chawla was the designer and lead investigator of the ATHOS (Angiotensin II for the Treatment of High Output Shock) trial which results led to the ATHOS 3 trial, (The Phase 3 clinical trial of angiotensin II, for the treatment of catecholamine-resistant hypotension). Additional Resources: ATHOS-3 Clinical Trial. Randomized controlled trial evaluating the efficacy of Angiotensin II in raising blood pressure in vasodilatory shock. http://www.nejm.org/doi/full/10.1056/NEJMoa1704154 Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II. https://www.ncbi.nlm.nih.gov/pubmed/?term=Outcomes+in+Patients+with+Vasodilatory+Shock+and+Renal+Replacement+Therapy+Treated+with+Intravenous+Angiotensin+II Prescribing information for Angiotensin II (GIAPREZA ™ ). http://giapreza.com/giapreza-prescribing-information.pdf Books Mentioned in This Episode: Atlas Shrugged: https://www.amazon.com/Atlas-Shrugged-Ayn-Rand/dp/0451191145/ref=sr_1_1?ie=UTF8&qid=1522104389&sr=8-1&keywords=atlas+shrugged+book

In our first episode, we discuss the potential role of Angiotensin II for treating shock and review the results of the ATHOS-3 clinical trial. Our guest is Stephen W. Trzeciak, MD, MPH. Dr. Trzeciak is Interim Chair of Internal Medicine and Head of Critical Care Medicine at Cooper University Health Care. Dr. Trzeciak holds academic appointments as Professor of Medicine and Professor of Emergency Medicine at Cooper Medical School of Rowan University. He is also a prolific investigator and author, with recognized expertise in the treatment of shock, early interventions in critical illness, and the interface between the emergency department and the intensive care unit. Additional Resources: - Sound Critical Care webinar on vasopressors. Please review for a more comprehensive discussion on current evidence-based vasopressor use in clinical practice. - ATHOS-3 clinical trial. Randomized controlled trial evaluating the efficacy of Angiotensin II in raising blood pressure in vasodilatory shock. - FDA press release. After recording this podcast, the FDA announced the approval of Angiotensin II.

Dr Paul Wang:                   Welcome to the monthly podcast, On the Beat, for Circulation: Arrhythmia, and Electrophysiology. I'm Dr Paul Wang, Editor-in-Chief, with some of the key highlights from this month's issue.                                                 Koji Miyamoto and associates conducted the AD-Balloon Study, which investigates the ideal number of free cycles during second-generation cryoballoon pulmonary vein isolation. In a prospective, multicenter, randomized clinical trial, the authors compared in 110 patients the addition of a three minute freeze after pulmonary vein isolation had been achieved to pulmonary vein isolation alone. Delayed-enhancement magnetic resonance imaging was also performed one to two months after the pulmonary vein isolation to assess the ablation lesions. The freedom from atrial arrhythmias at one year was similar. Log rank test, P equals 0.78 in the two groups, 87.3% in the extra three-minute freeze group, and 89.1% in the pulmonary vein isolation group. There was no significant difference in the frequency of gaps on the pulmonary vein isolation lines in the delayed-enhancement magnetic resonance imaging. The authors conclude that an insurance freeze after achieving pulmonary vein isolation may be unnecessary and time consuming.                                                 In our next study, Robert Sheldon and associates examined the genetic basis of vasovagal syncope. They studied 160 subjects in 9 kindreds comprising 82 fainters and 78 controls. Common genetic variants were genotype for 12 genes for vascular signaling, potassium channels, the serotonin 5-HT1A receptor, the serotonin transporter and catecholamine-O-methyltransferase or COMT. They found that in 9 of 12 variants, there was no significant association between genotype and phenotype. However, the serotonin 5-HT1A receptor, HTR1-A G alleles were associated with syncope in males but not in females. P equals 0.005. The men with serotonin 5-HT1 receptor C alleles had a 9% likelihood of syncope while Gg males had a 77% likelihood of syncope. The SL6A4 promoter L alleles were associated with decreased syncope in males but increase in females. P equals 0.059. The Ll males had a 25% syncope likelihood and Ss males had a 47% syncope likelihood. The COMT A alleles were associated with decreased syncope in males but increased in females. P equals 0.017. The Gg males had a 50% syncope likelihood and A males had a 15% syncope likelihood. The Gg females had 52% syncope likelihood and the Aa females had a 73% syncope likelihood. The authors concluded that there is a sex-dependent effect of alleles of serotonin signaling in vasovagal syncope, supporting the serotonin hypothesis of the physiology of vasovagal syncope.                                                 In the next study, Michael Barkagan and associates sought to examine whether the standard criteria for mitral line block with endocardial and epicardial activation mapping may not distinguish from slow conduction or conduction via epicardial bridging connections. In 56 patients, the authors creates a posterior mitral line using radiofrequency ablation. Mitral block determined by pacing with conduction block defined as trans-isthmus time of 100 milliseconds or greater in reversal of coronary sinus activation during pacing from the left atrial appendage was achieved in 51 out of 56 or 91% of patients. In 11 of 51 or 22% of patients, high-resolution activation mapping, using Rhythmia, of the endocardium and epicardium via the coronary sinus demonstrated residual endocardial in 27% or residual epicardial in 73% connections. Epicardial bridging connections were distant from the line, 2.4 plus or minus 1.6 centimeters, inserting laterally at the proximal-mid coronary sinus and septally at the left atrial ridge. Patients with residual conduction were prone to complex circuits involving the epicardium in 7 of 11 patients. Mitral line block was achieved in 75% by targeting these insertion sites. The trans-isthmus time had limited predictive value for distinguishing block from pseudoblock. The authors concluded the connections are a frequent cause of complex circuits, and their insertion sites can be targeted for ablation.                                                 In our next paper, Santiago Rivera and associates examined the causes of QRS variability in Papillary muscle arrhythmias usually attributed to anisotropy. In 33 patients with papillary muscle arrhythmias prospectively undergoing cardiac resonance imaging, papillary muscle connections away from the papillary muscle base were identified. Arrhythmogenic papillary muscles, N equals 35, exhibited a higher number of papillary muscle connections, 72 versus 18, P equals 0.01. Patients with inconsistent QRS precordial transition and inconsistent QRS access exhibited a 100% prevalence of papillary muscle connections. Those with consistent precordial transition and consistent QRS access showed 40% and 26% prevalence of papillary muscle connections respectively. Inconsistent QRS precordial transition and inconsistent QRS access predicted the presence of papillary muscle connections with 59% or 28% sensitivity and 100% specificity respectively. Those papillary muscles exhibiting clinical recurrence after ablation presented a higher prevalence of papillary muscle connections, 91% versus 60%, P=0.04.                                                 In our next paper, Jason Coult and associates examined the quantitative measures of the electrocardiogram waveform during ventricular fibrillation to assess myocardial physiology and predict cardiac arrest outcomes. They collected five second ventricular fibrillation ECG segments with and without chest compressions prior to 2,755 defibrillation shocks from 1,151 out of hospital cardiac arrest patients. 24 individual measures and 3 combination measures were optimized to predict functionally intact survival using 460 training cases. Measures predicted functionally intact survival in 691 independent test cases with an area under the receiver operating curve (AUC) ranging from 0.56 to 0.75 without chest compressions and 0.53 to 0.75 with compressions, P less than 0.001. Of all measures evaluated, the support vector machine model ranked highest both without chest compressions, AUC equals 0.75, and with compressions, AUC equals 0.75. The authors concluded the waveform measures predict functionally intact survival when calculated during chest compressions, but prognostic performance is generally reduced compared to analysis without compressions. Support vector machine models exhibited similar performance with and without compressions while also achieving the highest area under the curve.                                                 In our last paper, Hailey Jansen, Martin Mackasey and associates examined the effective natriuretic peptides in the specific natriuretic peptide receptor NPR-C on angiotensin II-mediated atrial fibrillation. The authors examined wild-type and NPR-C knockout mice to investigate the effects of angiotensin II administered three milligrams per kilo per day for three weeks on atrial fibrillation susceptibility and atrial function. In wild-type mice, angiotensin II increased susceptibility to atrial fibrillation and associated with a prolonged P wave duration, increased atrial refractory period, and slowed atrial conduction. These effects were exacerbated in angiotensin II-treated NPR-C knockout mice. Angiotensin II prolonged action potential duration and reduced action potential upstroke velocity. Angiotensin II also increased fibrosis in the atria in wild-type mice while angiotensin II-treated NPR-C knockout mice exhibited substantially higher atrial fibrosis. Co-treating wild-type mice with angiotensin II and the NPR-C agonist cANF, those dependently reduced atrial fibrillation inducibility by preventing some of the angiotensin II-induced changes in atrial myocyte electrophysiology and preventing atrial fibrosis. The authors suggested that the NPR-C receptor may represent a new target for the prevention of angiotensin II-induced atrial fibrillation via protective effects on atrial, electrical and structural remodeling.                                                 That's it for this month! We hope that you'll find the journal to be the go-to place for everyone interested in the field. See you next time! This program is copyright American Heart Association 2019.

Todd Fraser, MD, speaks with Rinaldo Bellomo, MD, MBBS, FRACP, FCICM, FAAHMS, about the article Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II

Todd Fraser, MD, speaks with Rinaldo Bellomo, MD, MBBS, FRACP, FCICM, FAAHMS, about the article Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II

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. This week's journal features important information, that will aide identification of children with latent rheumatic heart disease, who are at highest risk of unfavorable outcomes. This important discussion is coming right up after these summaries.                                                 The first original paper this week describes the largest study to date to examine payer approvals and rejections of PCSK9 inhibitor therapy, and describe the patient characteristics associated with successful prescribing. First author, Dr. Hess, corresponding author Dr. Yeh and colleagues from Beth Israel Deaconess Medical Center in Boston, Massachusetts, performed a retrospective descriptive cohort study utilizing nationwide pharmacy claims linked to electronic medical records from a nationwide data warehouse. The data set included over 220 million patients from all 50 states, and all pair types with more than 5,000 distinct health plans. PCSK9 inhibitor prescriptions were submitted for 51,422 patients in the pharmacy data set.                                                 The authors found that among patients who were prescribed a PCSK9 inhibitor, 47% were approved for coverage by the payer. Variables that were associated with approval included age above 65 years, history of atherosclerotic cardiovascular disease, prescription by a cardiologist or a non-primary care provider, statin intolerance, longer statin duration, and non-commercial payers. Interestingly, higher LDL cholesterol levels were not associated with higher approval rates. Commercial third-party payers had the lowest approval rates of 24 from 4% and Medicare had the highest at 60.9%. Thus, rates of approval for PCSK9 inhibitor therapy are low, even for patients who appear to meet labeled indications. While a combination of clinical characteristics increase the likelihood of approval, payer type is the most significant factor.                                                 The next study identifies a novel mitochondrial localized protein that plays a role in cardiac dysfunction, remodeling, and heart failure. This protein is FUN14 domain-containing 1, or FUNDC1, a highly conserved outer mitochondrial membrane protein. In today's study, first author, Dr. Wu, co-corresponding authors, Dr. Xie and Zou from Georgia State University, and their colleagues, showed that in cardio myocytes, FUNDC1 bound to inositol 1, 4, 5-triphosphate type 2 receptor, to form mitochondria-associated endoplastic reticular membranes.                                                 These, in turn, modulate a calcium release from endoplasmic reticulum into mitochondria and the cytosol. FUNDC1 deletion lowered the levels of calcium in both mitochondria and the cytosol. A reduction at intracellular calcium resulted in mitochondrial fusion, mitochondrial dysfunction, cardiac dysfunction, and heart failure. In summary, this study identifies FUNDC1 as a novel mitochondrial localized protein that plays a role in maintaining mitochondrial dynamics, and cardiac function, and may therefore be a therapeutic target in heart failure.                                                 The next study takes a deep dive into the J-Curve phenomenon of systolic blood pressure by providing an experimental approach to an observational paradigm. First and corresponding author, Dr. Kalkman, from University of Amsterdam and colleagues assess the association between on-treatment systolic blood pressure levels, cardiovascular events, and all cause mortality in patients randomized to different systolic blood pressure targets in the pool database of the SPRINT-6 and ACCORD trials. For both the intensive blood pressure target of less than 120 millimeters mercury, and the conventional target of less than 140 millimeters of mercury, the authors found an identical shape of the J-curve was present with a [inaudible 00:04:44] for cardiovascular events and all cause mortality just below the systolic blood pressure target.                                                 The advantage of the intensive treatment group persisted at any level of the difference between the intended target and the achieved blood pressure targets. As discussed in an accompanying editorial by Dr. Verdecchia from Hospital of Assisi in Italy, these data suggest that if two patients achieve identical low values of blood pressure during treatment, prognosis is expected to be better in the patient actually targeted to achieve low values. Conversely, the outcome might be worse in the patient randomized to a higher blood pressure target, because low values in this case possibly reflect masked or unmasked confounders linked to a poorer outcome.                                                 Thus, physicians should not be reluctant in lowering blood pressure in their patients because of an expected detrimental effect of BP reduction on death or major cardiovascular events. Rather, they should carefully monitor the possible occurrence of other adverse effects linked to blood pressure lowering, such as syncope, renal impairment, or electrolyte disturbances. This study further suggests that the benefit or risk associated with intensive blood pressure lowering treatment can only be established via randomized clinical trials and should not be extrapolated from observational data.                                                 The final study establishes a causal link between dysregulated Tryptophan metabolism and abdominal aortic aneurysm. In a series of elegant mouse experiments from first author, Dr. Wang, two corresponding authors, Dr. Liu] and Ding from Georgia State University in Atlanta, Georgia, the authors establish that 3-Hydroxyanthranilic acid or 3-HAA, a key Tryptophan catabolite of the Angiotensin II induced abdominal aortic aneurysm in vascular smooth muscle cells was indeed responsible for Angiotensin II induced abdominal aortic aneurysm in Vivo. 3-HAA activated nuclear factor kappa-B transcription factor, promoted matrix metallopeptidase 2 expression in vascular smooth muscle cells. Human abdominal aortic aneurysm samples had stronger staining with the antibody against 3-HAA, than those in the adjacent non-aneurysmal aortic sections of these samples.                                                 The identification of 3-HAA in Angiotensin II triggered abdominal aortic aneurysm and in human patients with abdominal aortic aneurysms, suggests that Tryptophan derived metabolites may be a biomarker for abdominal aortic aneurysm diagnosis. Furthermore, agents that alter Tryptophan metabolism may have a therapeutic potential in preventing or treating abdominal aortic aneurysms. Well on that intriguing note, we're at the end of this week's summaries. Now, for our featured discussion.                                                 Today's feature paper really reminds us that rheumatic heart disease remains the most common cardiovascular disease among the world's youth. These days, echocardiographic screening provides a promising tool for early detection. However, the utility of this tool really depends on knowing the natural history of screen detected rheumatic heart disease, so-called latent rheumatic heart disease. Now, that has remained clear until today's paper. I'm so pleased to have with us the first and corresponding author, Dr. Andrea Beaton, from Children's National Medical Center in Washington D.C., as well as Dr. Bongani Mayosi, Associate Editor from University of Cape Town, South Africa. Andrea, could you start by letting us know about your study and what you found? Dr. Andrea Beaton:         As you mentioned, over the last decade or so it's become clear that in addition to the substantial burden of clinical rheumatic heart disease that we see around the world in low and middle income countries, there's also an even larger burden of latent rheumatic heart disease or early rheumatic heart disease that we can see on echo. This brings up the question if echo screening might represent a very powerful tool for rheumatic heart disease control, but we can't move forward with that discussion until we understand the rate of progression of children who are found to have echo detected rheumatic heart disease, and if we can do something to intervene to prevent progression in that population.                                                 That something is likely penicillin, which is known to prevent progression in clinical rheumatic heart disease. To start to address that question, we followed a large cohort of children who had been diagnosed with echo detected rheumatic heart disease through school-based screening in different areas of Uganda and had collected about 227 cases of children with latent rheumatic heart disease who had been in clinical followup between two and a half and almost six years. Dr. Carolyn Lam:               Great. Could you tell us what you found about the progression and risk factors perhaps of progression, which I think are most significant? Dr. Andrea Beaton:         Right, so this is the largest natural history cohort of children with latent rheumatic heart disease to date and four major findings emerged from our study. The first is that we find a lot of echo detected rheumatic heart disease in low income settings that is more advanced. What we found is that children, even if this is their first time of diagnosis at echo screening, if they had moderate to severe rheumatic heart disease on screening, if they had poor outcomes even if over a very short time period. In our study, children with moderate to severe disease, only 10% of those children improved over the study period and 10% had died after only two to five years of followup.                                                 We also saw that kids with mild, but definite rheumatic heart disease, which is more criteria for rheumatic heart disease than borderline, showed worse outcomes. Although, both children with mild definite and borderline disease had substantial risk of progression. 25% progressed in the mild definite group and 10% in the borderline rheumatic heart disease group. That tells us that even with very minor changes on echo screening, there is substantial risk of progression to more severe rheumatic heart disease, because we had a larger cohort using a multi-variant model.                                                 We also found that there were features of rheumatic heart disease that put children at higher risk of progression. In our cohort, if children had aortic insufficiency at the time of screening, or some specific morphological changes, or changes in the mitral valve at time of screening, then they had higher risk of progression. While older age at time of screening showed a protective effect against progression. Dr. Carolyn Lam:               Wow. Andrea, congratulations on this remarkable study and you've highlighted so many important public health messages just in this one study. Bongani, what do you think was the most important or significant finding? Dr. Bongani Mayosi:        The most important finding is the reflection of the progression even in the mild and borderline cases. I think there has been an understanding that the definite cases do have a higher rate of progression and on top of that, I think showing the fact that there are some predictors that can be detected on echo is also very useful. Those with more advanced disease categories, those with younger age, as well as those with morphological valve abnormalities, I think those are very, very valuable points. Of course, the other point that is not all here is the fact that the majority of the initial progression appears to occur early and this is brought out in this study because of the serial echos that were done, which is again, another very valuable and a unique aspect of the study.                                                 Previous studies have only done an echo at the time of diagnosis and perhaps an echo at the end of the followup period. I think that these features really make this study a valuable one. There is one question though that I wanted to put to Andrea, the issue of auscultation is one that we realized very early was not very useful for screening patients with latent rheumatic heart disease. We missed too many. I'd like to ask you now, once we've identified patients with latent disease, do you think auscultation of those patients could in fact identify the ones with clinical disease? Presumably, the more severe aortic regurgitation, mitral regurgitation, may be audible using a stethoscope? In other words, now shifting the role of the stethoscope not so much for diagnosis, but for risk stratification. I just want to know if you looked at this issue at all in this particular cohort? Dr. Andrea Beaton:         That's a really good question, Professor. We did not specifically look at the role of auscultation in this cohort. Although, it stands to reason that children with moderate to severe rheumatic heart disease, which by our definitions meant at least moderate to severe regurgitation at one of the valves, or presence of mitral stenosis would be audible. In that way, I think separating out children with moderate to severe disease, versus children with mild definite and borderline disease, would be quite possible and reasonable by auscultation.                                                 My worry with the use of auscultation is I don't think it would separate out well children with mild definite disease, who by definition could have no more than mild regurgitation at any one valve, from children with borderline disease. Whether that distinction is important, I think still remains to be understood, but it would not be a very sensitive way to follow children until they had progressed to the point of having much more significant disease. I think echo still remains incredibly sensitive compared to auscultation for minor progressions, which to be clear, were included here as counting as progression of disease, even minor changes on echocardiographic evaluation. Dr. Carolyn Lam:               I have a question along the same lines Andrea, what kind of expertise was required for these echocardiographic screening procedures, both of the acquisition and then the interpretation? I do notice that you had a trained pediatric cardiologist with expertise in rheumatic heart disease who actually re-reported some of the echos. Do you think this is needed? What do you think about that? Dr. Andrea Beaton:         This is a complicated question, but a good one. A lot of the research that we've done outside of this paper has been looking at the ability to task shift echo screening, so to have non-physicians, not experts conducting echo screening. What we found across the board, as well as other groups around the world have found, is that you can train non-experts in a relatively short period of time to both screen and diagnose, at least on a screening basis, the presence of absence of rheumatic heart disease. For the purposes of this study, we're using very precise and very detailed diagnosis. According to the World Heart Federation criteria, which do really require experts to interpret. Dr. Bongani Mayosi:        The other issue, Andrea, which you highlight in the paper is the whole issue of the definition of progression, and regression, and the fact that there isn't consensus in the field about how we handle that, which results in papers not being comparable among each other. What do you suggest is the way of taking this forward so that we can build a consensus and a way of actually following up this patients that will be comparable between studies? Dr. Andrea Beaton:         That's a really important question and something we struggled with while we were writing this paper. You'll note in our paper that we reported it in two different ways because we couldn't come to a consensus and we thought both had some legitimate importance. Most of the papers in this field have reported the groups as progression and as stable lumped together, versus regression or improvement of disease. We felt the most important endpoint and something we had the numbers to power, was progression by itself. How many children were getting worse over the study period? In one sense, we powered it progression, versus stable plus regression, trying to dichotomize it still.                                                 Then on the other hand, we thought that it was important if you had mild definite disease, even if you remained stable and mildly definite, and so we reported differently on the second outcomes based on if you had definite disease where we grouped progression and stable together, versus if you had borderline where we only counted true progression as a change for the worse. I don't have the perfect answer of how this should be reported. Although, I think the more granular we can be as we report these studies going forward, the more we can separate out the data that is reported to make it comparable. A lot of the previous papers, I think, lack the granularity needed to compare in different ways. Dr. Carolyn Lam:               We're coming to the end of our time, so may I just wrap up by asking Andrea, what do you think are the next steps? Dr. Andrea Beaton:         That's a good question and something I feel strongly about. Another part of our paper showed that the other incredibly important outstanding question is if we can find these kids, can we change what happens to them over time, and does penicillin do that? Even with our large cohort of patients, we couldn't determine the effect of penicillin on progression or trajectory of these children over this time period. It's something that now that we have large numbers of children and still can't come to a conclusive response, I think warrants a randomized control trial to look at the effect of penicillin on children with echo detected rheumatic heart disease, because that's really what's going to drive the policy on if echo screening makes sense as a public health policy to reduce the global rheumatic heart disease burden. Dr. Carolyn Lam:               I'm sure listeners out there, you've appreciated this as much as I have. Tune in again next week.

Bisher wurden sieben verschiedene TRPC-Kanäle (für „classical (oder canonical) transient receptor potential“) beschrieben, die in der Plasmamembran tierischer Zellen lokalisiert sind. Diese Kanäle gehören zu einer von sieben Familien der TRP-Ionenkanäle, deren Mitglieder an einer Vielzahl von physiologischen Funktionen im Körper beteiligt sind. Im Jahr 2005 konnten in Patienten, die an einer autosomal dominant vererbten Form der fokalen segmentalen Glomerulosklerose (FSGS) leiden, Mutationen der TRPC6-Kanäle identifiziert werden, die zu einer Überaktivität dieser Kanäle führen ( sog. “gain-of-function”-Mutationen). Etwas später (2006) wurden aber auch einige FSGS Patienten entdeckt, die keine „gain-of-function“-Mutationen im TRPC6 sondern funktionslose, sog. „loss of function“-Mutationen der Phospholipase Cɛ (PLCɛ) exprimierten. Diese Daten deuten auf eine funktionelle Interaktion zwischen TRPC6 und PLCɛ in Zellen der Niere hin, die bisher noch nicht näher untersucht worden ist. Beide Proteine könnten sich auch als Zielstrukturen für eine Pharmakotherapie der FSGS eignen. Die FSGS äußert sich durch eine Störung des glomerulären Filtrationsprozesses in der Niere, wodurch es unter anderem zu einer Proteinurie kommt. In vielen Fällen führt die FSGS terminal zur ESRD („end stage renal disease“), also zu einem akuten Nierenversagen. Glomeruli bilden die filtrierende Einheit der Niere, wobei der eigentliche Filter, welcher im Inneren des Glomerulus lokalisiert ist, aus Podozyten, Endothelzellen und der dazwischen befindlichen Basalmembran besteht. Da TRPC-Kanäle unter anderem in Podozyten exprimiert werden, liegt die Annahme nahe, dass diese Zellen durch den vermehrten Ca2+-Einstrom mutierter Kanäle bei der FSGS krankhaft verändert sein könnten. Aus diesem Grund wurden in dieser Arbeit Podozyten aus Wildtyp (WT)-Mäusen sowie TRPC6 (TRPC6-/-)- und PLCε (PLCε-/-)-gendefizienten Tieren isoliert und umfangreich durch den Nachweis podozytenspezifischer Markerproteine charakterisiert. Zellfunktionen wie Proliferation, Aktinstressfaserbildung, RhoA- und TRPC6-Aktivität wurden vergleichend in den Zellen der verschiedenen Genotypen analysiert. Es zeigte sich, dass PLCε zwar mit TRPC6 in Zellen des Nierenkortex interagieren kann, aber PLCε-/--Podozyten funktionell in ihrer Angiotensin II-induzierten Aktinstressfiberbildung und GTPγS-induzierten TRPC6-Aktivierung nicht von Wildtyp-Podozyten unterschieden werden konnten, was auf eine redundante Funktion der PLCε-vermittelten TRPC6-Aktivierung hindeutet. Eine Aktivierung von TRPC6 durch PLCε wird wahrscheinlich durch die Stimulation der wesentlich stärker exprimierten anderen PLC-Isoform PLCβ1, zumindest in Podozyten, überdeckt. Eine Expression der klonierten murinen TRPC6-FSGS-Mutanten in primär isolierten Wildtyp- und TRPC6-defizienten Podozyten war für die Zellen lethal, wodurch die Pathogenität eines erhöhten TRPC6-induzierten Ca2+-Einstroms für diese Zellen und damit den gesamten Nierenglomerulus in FSGS-Patienten noch einmal nachgewiesen werden konnte. In Zukunft könnten deswegen spezifische TRPC6-Inhibitoren eine Therapieoption zur Linderung der Symptome bei FSGS-Patienten sein.

Dr. R. Wayne Alexander. Angiotensin II, Oxidative Stress and Vascular Biology. Recorded 2013-09-09.

TRPC-Kanäle 1-7 wurden bisher als unselektive Kationenkanäle in heterologen Expressionssystemen beschrieben. Ihre physiologische und pathophysiologische Rolle in verschiedenen Organen und Geweben des menschlichen Körpers ist aber noch weitgehend unklar. Ziel dieser Arbeit war es, die Funktion zweier Mitglieder der TRPC-Familie, TRPC1 und TRPC6, in verschiedenen Zellsystemen mit Hilfe von Untersuchungen an den entsprechenden gendefizienten Mausmodellen näher zu analysieren. Nach der Klonierung der codierenden Sequenz des murinen TRPC1-Proteins aus Mausgeweben, wurden murine embryonale Fibroblasten (MEFs) aus TRPC1-defizienten und Wildtyp-Mäusen isoliert. Ein Vergleich zeigte, dass das Fehlen des TRPC1-Kanals die Viabilität dieser Zellen signifikant steigerte und die Wundheilungsrate signifikant herabsetzte. Durch die Identifikation sogenannter überaktivierter TRPC6-Kanal-Mutanten in Patienten mit fokaler segmentaler Glomerulosklerose (FSGS) war dann insbesondere die Funktion dieses Kanals in den Podozyten der Niere von besonderem Interesse. Wenig später wurden auch funktionslose Mutanten der Phospholipase C-e (PLCe) in Patienten mit dem gleichen oder einem ähnlichen Krankheitsbild beschrieben, das zu einer Erhöhung des Serumproteingehalts im Urin (Proteinurie) führt. Zur Beantwortung der Frage, ob beide Proteine interagieren und Komponenten eines gemeinsamen Signalweges sind, wurden primäre Podozyten aus Mäusen isoliert. In der Tat wurde in primären Podozyten und in HEK293-Zellen eine Interaktion beider Proteine identifiziert und ein möglicher Signalweg von der Aktivierung des Angiotensin 1-Rezeptors zum PLCe-induzierten Calciumioneneinstrom durch TRPC6-Kanäle aufgezeigt. Darüber hinaus wurden TRPC6-, PLCe- und TRPC6/PLCe-defiziente Podozyten mit Wildtyp-Podozyten in funktionellen Testsystemen verglichen. Zunächst konnte eine vermehrte Expression von TRPC4- und TRPC5-Kanälen in PLCe-defizienten und TRPC6/PLCe-defizienten Podozyten identifiziert werden. Außerdem zeigte sich in ersten Untersuchungen, dass das Fehlen des TRPC6-Kanals zu einer erhöhten Zellviabilität und zu einer verminderten Apoptoserate der Podozyten führte. In sog. Calcium-Imaging-Experimenten wurde ein stark reduzierter Calciumioneneinstrom in TRPC6- und PLCe-defizienten Podozyten nach AT1-Rezeptoraktivierung durch Angiotensin II beobachtet. Da Podozyten durch ihre Barrierefunktion wesentlich zur Stabilität des glomerulären Filters beitragen, wurde auch die Veränderung des Zytoskeletts durch Aktinpolymerisation näher untersucht. Es zeigte sich, dass Podozyten nach Applikation von Angiotensin II durch eine stärkere Polymerisation von globulärem Aktin vermehrt sog. Aktin-Stressfibern ausbilden und abflachen. TRPC6-defiziente Podozyten hingegen zeigen bereits im Ruhezustand deutlich mehr Aktin-Stressfibern, die nach Gabe von Angiotensin II nicht mehr signifikant in ihrer Anzahl zunehmen. Die Daten der vorliegenden Arbeit sind im Einklang mit der Hypothese, dass ein zu starker Calciumioneneinstrom in Podozyten durch überaktivierende TRPC6-Mutationen zu einer geringeren Podozytenstabilität und zu einer erhöhten Apoptoserate führen kann. Die mangelnde Stabilität des glomerulären Filters in den FSGS-Patienten führt dann zu einer Proteinurie und schließlich zum Nierenversagen. Durch Expression der TRPC6-Mutationen in TRPC6-defizienten Podozyten könnte sich in Zukunft die Rolle des Kanals als wichtige pharmakologische Zielsubstanz für eine Pharmakotherapie der FSGS bestätigen.

Es wurden die hämodynamischen, biochemischen und morphologischen Effekte einer Angiotensin-II-Rezeptorblockade mit dem AT1-Blocker Losartan auf eine hypoxie-induzierte rechtsventrikuläre Hypertrophie an der Ratte untersucht. In weiblichen „Sprague Dawley“ Ratten wurde eine isolierte rechtsventrikuläre Hypertrophie durch intermittierende Hypoxie hervorgerufen. Die intermittierende Hypoxie bewirkte einen Anstieg des rechtsventrikulären Drucks und eine Erhöhung des Verhältnisses von Ventrikelgewicht zu Körpergewicht im rechten Ventrikel, die Hypoxiebehandlung hatte keinen Einfluss auf die linksventrikulären Kreislaufparameter oder das Herzzeitvolumen. Die Aktivitäten der Glukose-6-Phosphat Dehydrogenase und der 6-Phosphoglukonat-Dehydrogenase waren nach der Hypoxiebehandlung im rechten Ventrikel erhöht, jedoch nicht im linken Ventrikel. In der Hypoxiegruppe ohne Losartan war das Zellvolumen der isolierten Kardiomyozyten erhöht, die Kardiomyozytenzellänge unverändert, so dass man von einer hypoxieinduzierten rechtsventrikulären Hypertrophie vom primär konzentrischen Typ ausgehen muss. Losartan verringerte den hypoxie-induzierten Anstieg des rechtsventrikulären systolischen Druckes, die Zunahme des Verhältnisses von rechtsventrikulärem Gewicht zu Körpergewicht und die Enzymaktivitätserhöhung signifikant, wenn auch nicht vollständig. Die Zunahme des Volumens und der Querschnittsfläche der isolierten Kardiomyozyten wurde durch Losartan jedoch vollkommen verhindert.

Entwicklungsbiologen haben vor über 25 Jahren festgestellt, daß Progesteron (PROG) die Fortsetzung der Reifeteilung an Xenopus Oozyten durch nicht-genomische Mechanismen an der Plasmamembran initiiert. Obwohl mehrere Publikationen dabei keine oder nur späte Veränderungen der intrazellulären Calciumkonzentration [Ca2+]i beschreiben, konnten Wasserman et al. an einigen Oozyten [Ca2+]i-Erhöhungen innerhalb der ersten Minute nach PROG-Zugabe beobachten. Diese Versuche sollten mit der Methode des Calcium Imaging reproduziert werden, wobei der Verlauf von [Ca2+]i durch Fluoreszenzmessung und dem Ca2+-Indikatorfarbstoff Fura-2 gemessen wurde. Dabei konnten innerhalb der ersten Minuten nach PROG-Zugabe keine Veränderungen von [Ca2+]i gefunden werden. Lysophosphatidylsäure (LPA) hingegen löste sehr zuverlässig Calcium-Signale aus. Durch Thrombin, Angiotensin II und Acetylcholin ausgelöste Effekte ließen sich, wenn auch seltener, ebenfalls zeigen. Xenopus Oozyten sind molekularbiologisch als eukaryontisches Expressionssystem nutzbar. Zur Etablierung des Expressions- und Testsystems wurde RNA in die Oozyten injiziert, die für den GnRH-Rezeptor kodiert. Nach erfolgreicher Expression steigt [Ca2+]i 1-3 Minuten nach der Rezeptorbindung über eine Aktivierung von Phospholipase Cb und das InsP3 System an. Auch bei Injektion von weniger als 0,5ng RNA pro Oozyte in das Zytosol konnte nach zwei Tagen, bei weniger als 0,15ng nach vier Tagen, ein schnelles Ca2+-Signal auf GnRH-Zugabe gesehen werden. Ebenso zeigten diese Effekte auch Oozyten, bei denen ein eukaryontischer GnRH-Rezeptor-Expressionsvektor in den Kern mikroinjiziert wurde, nicht aber unbehandelte Oozyten oder andere Negativkontrollen. An glatten Gefäßmuskelzellen (RSMC) kann in vitro eine schnelle Erhöhung von [Ca2+]i auf Aldosteron (ALDO) und an Spermatozoen auf PROG gezeigt werden. Zur Anwendung des Expressionssystems auf schnelle nicht-genomische Steroideffekte wurde einerseits aus diesen Zellen isolierte RNA in den Oozyten exprimiert, als auch RNA, welche für ein membranständiges Progesteron-bindendes Protein (mPR) kodiert. Durch Expression von RSMC-RNA konnte an Oozyten allerdings keine Calciumreaktion auf ALDO beobachtet werden; ebensowenig auf PROG durch Expression von RNA aus Mäusehoden oder mPR-RNA. Die hier vorgestellte Methode ist daher weniger geeignet zur Screening-Untersuchung bei der Expressionsklonierung zur Isolierung putativer Rezeptoren aus Genbanken oder Gesamt-RNA. Insgesamt handelt es sich jedoch um ein sehr gutes System, die Expression eines Rezeptors funktionell nachzuweisen; weitere Untersuchungen zur Rezeptoraktivierung, Signaltransduktion und topographischen Signalausbreitung lassen sich anschließen.

Die vorliegende Arbeit beschäftigt sich mit dem Einfluss von Drogenextrakten und Naturstoffen auf die endotheliale NO-Synthase (eNOS) in humanen Endothelzellen (Primärkulturen und Zelllinien). Insbesondere wurde dabei ihr Einfluss auf den verschiedenen zellulären Ebenen (Transkription, Proteinexpression, NO-Synthese) untersucht. Da es in dieser Arbeitsgruppe die erste Arbeit auf dem Gebiet der eNOS war, mussten zunächst Methoden etabliert und entwickelt werden, mit denen die eNOS auf den verschiedenen zellulären Ebenen detektiert werden kann. Etabliert wurden ein Luciferase-Reportergen-Assay zur Messung der eNOS Promotoraktivität, eine Northern Blot-Methode zur Bestimmung der eNOS-mRNA und eine Western Blot-Methode zur Messung der eNOS Proteinmenge. Entwickelt wurden ein L-Arginin/L-Citrullin Umwandlungsassay zur Bestimmung der eNOS-bedingten L-Citrullin-produktion und ein DAF-2 Fluoreszenzassay zur Messung der eNOS-bedingten NO-Produktion. Getestet wurden Extrakte und Naturstoffe, bei denen bereits positive kardiovaskuläre Eigenschaften wie Vasodilatation bekannt bzw. in der Diskussion waren. Keinen Einfluss auf die eNOS hatten: •Knoblauchextrakte und schwefelhaltige Knoblauchextraktinhaltsstoffe •Der Weißdornblüten- und Blätterextrakt WS1442 •Die Catechinderivate Epicatechin-3-gallat und Epigallocatechin-3-gallat •Die Rotweinpolyphenole Delphinidin, Quercetin, Epicatechin und Rutin Dagegen konnten Isoflavone der Sojabohne, wie Genistein, Daidzein, Formononetin, Biochanin A und Equol die eNOS Promotoraktivität konzentrationsabhängig erhöhen. Genistein (stellvertretend für alle Isoflavone im Western Blot getestet) erhöhte auch die eNOS Proteinmenge. Allerdings bewirkte Genistein, trotzt der Erhöhung der Proteinmenge, keine Erhöhung der eNOS abhängigen Bildung an L-Citrullin und NO. Positive Ergebnisse brachten die Tests mit einem Rotweinpolyphenolextrakt (RWPE). Dieser Extrakt erhöhte signifikant die NO-Produktion in den beiden getesteten Endothelzellarten (EA.hy926 Zellen und HUVECs). Um den molekularen Mechanismus der NO-Produktionserhöhung durch RWPE aufzuklären, wurden verschiedene Ebenen der eNOS Regulation untersucht. Dabei konnte in dieser Arbeit zum ersten mal gezeigt werden, dass RWPE sowohl die eNOS Promotoraktivität als auch die eNOS Proteinexpression erhöht. Die nächste Frage war, ob die NO-Produktionserhöhung kausal mit der gemessenen Transkriptionserhöhung zusammenhängt. Zeitabhängige Untersuchungen auf den verschiedenen Ebenen der eNOS Regulation ergaben ähnliche Ergebnisse mit einer signifikant messbaren Beeinflussung stets nach ca. 10 h. Dies deutet darauf hin, dass RWPE die eNOS-abhängige NO-Produktion über eine Erhöhung der eNOS Transkription/Translation erhöht. Allerdings konnte dies auf Grund fehlender Experimente über eine posttranslationelle eNOS Beeinflussung nicht eindeutig bewiesen werden. Abschließend sollte mit der Suche nach den wirksamen Bestandteilen im RWPE begonnen werden. Auch wenn im Verlauf dieser Arbeit die wirksamen Verbindungen noch nicht gefunden wurden, konnten zumindest einige Substanzen als wirksamkeitsbestimmend oder -mitbestimmend ausgeschlossen werden. Neben einigen nicht wirksamen Rotweinpolyphenolen (Delphinidin, Rutin, Quercetin, Epicatechin) geben die durchgeführten Experimente Hinweise darauf, dass auch Anthocyane, Tannine und oligomere Procyanidine unwirksam sind. Das Stilbenderivat Resveratrol, welches oft als eine kardiovaskulär aktive Komponente im Rotwein angesehen wird, hatte nur einen sehr geringen und auf der Ebene der NO-Produktion nicht signifikanten Effekt auf die eNOS. Zusammenfassend wurde in dieser Arbeit ein Modell zur Messung von Einflüssen auf die eNOS aufgebaut. Von den getesteten Extrakten und Naturstoffen beeinflusste nur RWPE signifikant die eNOS. Es konnte erstmalig gezeigt werden, dass RWPE in Endothelzellen nach Langzeitstimulation (20 h) die eNOS Transkription, eNOS Expression und eNOS bedingte NO-Produktion erhöht. Dieses Ergebnis ist physiologisch äußerst interessant. Denn bisher bekannte, die eNOS Expression erhöhende Substanzen (z.B: Östradiol, Cyclosporin A, Insulin, Phorbolester, Wasserstoffperoxid, Staurosporin, Angiotensin II) sind auf Grund ihrer vielseitigen physiologischen/toxischen Wirkungen therapeutisch zur Prophylaxe und Behandlung von kardiovaskulären Erkrankungen kaum einsetzbar. Die Aufgabe zukünftiger Arbeiten wird es sein, die Wirkung von RWPE in vivo zu untersuchen und die für die Wirkung verantwortlichen Bestandteile des RWPE zu finden.

Fri, 1 Jan 1999 12:00:00 +0100 https://epub.ub.uni-muenchen.de/16617/1/10_1159_000045257.pdf Lang, Susanne M.; Schiffl, Helmut