Podcasts about omland

This week please join author Barry Borlaug and Associate Editor Torbjørn Omland as they discuss the article "Evidence-Based Application of Natriuretic Peptides in the Evaluation of Chronic Heart Failure With Preserved Ejection Fraction in the Ambulatory Outpatient Setting." For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250407.806254

Join Jen, Greg, and Cory as we chat with Nikolas Omland of Vision PRC

This week, please join author Leslie Gordon and Associate Editor Torbjørn Omland as they discuss the article "Plasma Progerin in Patients With Hutchinson-Gilford Progeria Syndrome: Immunoassay Development and Clinical Evaluation." For the episode transcript, visit:  https://www.ahajournals.org/do/10.1161/podcast.20230601.394643        

Are you embracing herbs for midlife? Herbs and herbal remedies can be utilized at any age! They are specifically wonderful in menopause, when stress, digestion, and hormone changes might wreak havoc on our well being. This episode will: Describe Herbalism, from Correne's perspective. Share Correne's story of depression, conventional medicine (which we agree we NEED!) and how herbs were the catalyst that helped her feel alive again. Give a brief introduction to herbs, from a physical and energetic perspective. Discuss the foundation of the gut. Teas, capsules or tinctures? What's best? The simplest way to start. Correne is a clinically trained herbalist, keeper of the home, food grower & preserver, light worker and practitioner of ancient Germanic traditions and ways. She is proud to serve her community in Kawartha Lakes, Ontario. Her family resides on a small-scale homestead that produces much food, medicines, joy and of course, a touch of magic.  Correne is passionate about self-sufficiency, continual growth and learning and sharing what small sprinkles of wisdom she gleaned through the years. Join her on this journey and discover the bliss that can be found through plants, hearth & home and honouring ancestral ways.  Full Show Notes on the Website View this on YouTube Visit Spirea Herbs Connect with Correne on YouTube Connect with Correne on Instagram  

Ukens pod med Barstad, Gnatt og Omland.

Programledere: Jon Åge Skuland, Terje Kingsrød Gjester: Dag Øyvind Juliussen, Geirr Standal, Jan Olav Hansen, Trine Overå Hansen, David Sagen, Ingjerd Omland

We've heard about sound healing with Tibetan bowls, tuning forks, and Chakra bowls, but today we are discussing the power of New Age music when listened to intentionally with producer and artist David Vito Gregoli. And you will hear here, some of Vito's soundbites from his latest work. What is New Age music? It's a tremendously large sector of music often used in yoga classes, massage and spas, but the unique quality of New Age is that it speaks to your heart and brings you to a state of internal awareness. This is music that doesn't tell you how to feel, but allows you to feel what you feel.Many people think New Age is limiting to those who only practice alternative therapies or traditions, but this is a new kind of love song. World influence, chanting, ambient, flowing, dramatic and healing would be words that come to mind in describing this beautiful genre.Vito's musical journey began in Pop, Rock and Blues. By the time he was in his teens, he was already hailed as a guitar virtuoso and working regularly in the L.A. club scene. He later studied classical music and received a Bachelors in Music from CSUN. Vito's latest release is with 2x Grammy winner and environmentalist Ricky Kej. “Wild Monsoon” drops in June 2022. It's a eclectic blend of World Beat and New Age.Ricky and Vito paired last on Vito's “Om Land” album.Vito brings integrity and unique artistry to music that defies pigeon-holes. "I have the ability to hear something in everything I can see round the bend when someone plays me an idea. That inspires me in the job of Producer." For more of Vito's work, go here. For more information about Leah's work, please go here. 

This week, please join author Christan Mueller, editorialist Christopher deFilippi, and Associate Editor Torbjørn Omland as they discuss the research article "Skeletal Muscle Disorders: A Non-cardiac Source of Cardiac Troponin T" and the editorial "Skeletal Muscle Disorders: A Non-cardiac Source of Cardiac Troponin T." Dr. Greg Hundley: Welcome, listeners, to this June 14, 2022, version of Circulation on the Run. I am Dr. Greg Hundley, associate editor and director of Poly Heart Center at VCU Health in Richmond, Virginia. This week I don't have my good friend Carolyn with me, but we will grab a cup of coffee and work through several of the articles in the issue. Dr. Greg Hundley: Well, first, I want to tell you about the feature discussion today, and we're going to interview with Christian Mueller and talk about the utility of cardiac troponin T and its association with an elevation in those individuals with skeletal muscle disorders, but, before we get to that, let's go through some of the other articles in this issue. Dr. Greg Hundley: Listeners, the first study comes to us from Professor Haidong Kan from Fudan university. These investigators conducted a time stratified, case crossover study among 1,292,000 acute coronary syndrome patients from 2,239 hospitals across 318 Chinese cities between January 1 of 2015 and September 30 of 2020 to determine the associations between sub-daily or hourly levels of criteria air pollutants with the onset of an acute coronary syndrome. Dr. Greg Hundley: Now, hourly concentrations of fine particulate matter, coarse particular matter, nitrogen dioxide, sulfur dioxide, carbon monoxide and ozone were collected, and the hourly onset data of acute coronary syndrome and its subtypes including ST segment elevation myocardial infarction, non-ST segment elevation myocardial infarction and unstable angina were obtained. Dr. Greg Hundley: Listeners, what did the investigators find? Well, their results indicated that transient exposure to the air pollutants of fine particulate matter, nitrogen dioxide, sulfur dioxide, and carbon monoxide, but not coarse particular matter or ozone may trigger the onset of acute coronary syndrome even at concentrations below the World Health Organization Air Quality Guidelines. Now, greater magnitude of associations were observed among patients that were older than 65 years in age or those without a history of smoking or chronic cardiorespiratory diseases and those in the cold seasons. Dr. Greg Hundley: Listeners, next, we're going to move from the study of air pollution to the world of preclinical science. Listeners, this study comes to us from Dr. Ming-Hui Zou from Georgia State University. Indoleamine 2,3-dioxygenase 1 or IDO1 is the rate limiting enzyme for tryptophan metabolism. IDO1 malfunction is involved in the pathogenesis of atherosclerosis, and vascular smooth muscle cells with an osteogenic phenotype promote calcification and features of plaque instability, but it remains unclear whether aberrant IDO1-regulated tryptophan metabolism causes vascular smooth muscle cell osteogenic reprogramming and arterial calcification. Dr. Greg Hundley: Listeners, what did this study find? Well, this investigative team and their results revealed the previously unrecognized protective role of IDO1 in arterial calcification in that vascular smooth muscle cells defective of IDO1 result in enhanced runt-related transcription factor 2 and ectopic calcium deposition in plaques. In contrast, administration of kynurenine via intraperitoneal injection markedly delayed the progression of intimal calcification in parallel with decreased RUNX2 expression. Dr. Greg Hundley: Also, listeners, the authors found that patients with coronary artery calcification have abnormal tryptophan metabolism, and serum IDO1 activity was inversely associated with calcification development in clinical settings, so, listeners, what are the clinical implications here? Well, this work reveals a protective role for IDO1 in mitigating arterial intimal calcification through kynurenine production and then, secondly, developing interventions toward the IDO1 kynurenine RUNX2 access may prevent the pathogenesis of arteriosclerotic complications. Dr. Greg Hundley: Well, listeners, a really interesting article, and now let's turn our attention to some of the other articles in the issue. Well, first, there's a Research Letter from Professor Modarai entitled “A Higher Incidence of Chromosomal Aberrations in Operators Performing a Large Volume of Endovascular Procedures,” and then, also, there is an AHA Update from our exiting AHA president who addresses “What Does the American Heart Association Do (and How Can You Help)?” Well, now, listeners, let's turn now to our feature related to a discussion of the utility of troponin T as well as troponin I in those with skeletal muscle disorders that may also present with acute coronary syndromes. Dr. Greg Hundley: Welcome, listeners, to this June 14 issue, and we're very excited today. We have with us Dr. Christian Mueller from the University Heart Center at Basel, Switzerland, Dr. Torbjorn Omland from the University of Oslo in Oslo, Norway, and Dr. Chris deFilippi from Inova Heart and Vascular Institute in Falls Church, Virginia. Dr. Greg Hundley: Welcome, gentlemen, and, Christian, we'll start with you. Could you describe for us some of the background information that went into your study, and what was the hypothesis that you wanted to address? Dr. Christian Mueller: Thank you very much for giving me the opportunity in this podcast to discuss our study with you and together with Torbjorn and Chris, who both contributed so enormously to the field with their own research. It's about cardiac troponin, cardiac troponin, an essential pillar in our early diagnosis of myocardial infarction. In this specific study, we tried to address possible non-cardiac causes of cardiac troponin T. In our clinical practice, we use and guidelines recommend both cardiac troponin T and I more or less as equivalent in providing identical information and, when going back from the clinical practice to biology, we have learned that, the troponin complex, that it is composed of three isoforms, T, I, and C. Dr. Christian Mueller: While they are very similar in their function, they are distinct regarding amino acid sequence in configuration in cardiac and skeletal muscle. As the cardiac form, of course, is the one that we are interested in, cardiac-specific assays have been developed both for cardiac troponin T and cardiac troponin I. As with any other tests in medicine, they are very good, but they may have limitations, and the specific questions that we had set for this study is whether skeletal muscle disease might be non-cardiac source for cardiac troponin T as measured in blood, therefore, with the possible harm of having false positive increases that could lead to a misdiagnosis of acute myocardial infarction. Dr. Greg Hundley: Very nice. We're trying to understand the utility of cardiac troponin T measures in those individuals that may have concomitant skeletal muscle disorders. Christian, what was your study population, and describe for us your study design? Dr. Christian Mueller: Our study had two components, a clinical component and a translational component. The clinical component included 211 consecutive patients that presented with active and chronic muscle symptoms to a workup either with a rheumatologist or a neurologist or internal medicine specialist, so more or less elective workup for muscle, skeletal muscle symptoms, to have a population that is broad and reflects all possible skeletal muscle disorders, their possible impact on cardiac troponin T concentration. Dr. Christian Mueller: In this population, we quantified cardiac involvement as this is common in some of these musculoskeletal disorders to be either major, minor or are not. They're according to patient history, according to … ECG and cardiac imaging, and we did the measurement of high sensitivity cardiac troponin using the high sensitivity cardiac troponin T assays used all over the world and three high sensitivity cardiac troponin I assays to look for mismatches, the percentage of patients that might have elevated T concentration, but not I as a possible sign that the T might be from the muscle, not the heart, particularly in those patients that didn't have any imaging evidence of cardiac involvement, and then we correlated the amount of high sensitivity cardiac troponin T with the amount of muscle injury as quantified by CK. Dr. Christian Mueller: In the translational part, those patients who have received a skeletal muscle biopsy with quantified by differential gene expression, the MRNA of the cardiac isoform of cardiac troponin T as well as of I in those patients who had the biopsy and matched it and compared it to controls to see whether the cardiac isoform would be upregulated in those with the cases of skeletal muscle disease. Dr. Greg Hundley: Very nice, and so, Christian, was this one single measurement at one point in time or did you have a series of measures over time? Dr. Christian Mueller: In fact, this is a large, ongoing project where patients will receive followup appointments. The current study reports the first phase versus single measurement at a single time point was performed. Dr. Greg Hundley: Very good. Christian, what did you find? Dr. Christian Mueller: We first found that even in those patients with active skeletal muscle disease, cardiac troponin T still reflected the presence of cardiac disease. Those patients with severe cardiac disease did have significantly higher concentration than those patients with mild or with no cardiac disease. That was the good thing. However, the more challenging one for this biomarker in this setting is that high sensitivity cardiac troponin T was significantly higher in these patients as compared to controls. We had the chance to have a couple of thousand controls from another study that presented with non-cardiac chest and no skeletal muscle disease and, while high sensitivity troponin I concentrations were similar, cardiac troponin T was elevated, resulting in a much higher prevalence of elevated T concentration versus elevated I concentration and corresponding mismatches in these patients. Dr. Christian Mueller: In the second part, we were able to show that there was a significant correlation between high sensitively cardiac troponin T with CK quantifying somehow muscle damage while this was not seen in the correlation with high sensitivity I, and that signaled that some of the systemic cardiac troponin T concentration seems to be derived from the muscle. It was confirmed in the translational part of the study in which the differential gene expression showed an eightfold over-expression of cardiac troponin T in skeletal muscle biopsies of those patients with disease, so with active skeletal muscle disease. This … expression correlated with disease activity, a pathological score that quantifies the extent of damage in the skeletal muscle history and correlated with the high sensitivity cardiac troponin T plasma concentration measured with the immunoassay. Dr. Greg Hundley: Very nice. Listeners, it sounds as if, in patients with skeletal muscle disorders, Christian's team observed an elevation in cardiac troponin T, but not necessarily cardiac troponin I, and you've got mechanistic understanding from the biopsies where you see this cardiac troponin T expression in the damaged skeletal muscles. Well, Torbjorn, you have many papers come across your desk. What attracted you to this particular paper? Torbjorn Omland: Thank you, Greg. I think, in general, when I receive papers from circulation, there are three main criteria I consider. The first is whether this is an interesting research question and then, second, whether the study is well-designed and the third is whether they're in themselves are novel, robust and interesting with potential clinical implications. Torbjorn Omland: For this specific papers, I must say it seemed to me to fulfill all these criteria and that it would be able to bring this field forward. The study of re-expression of troponin T in skeletal muscle is not entirely novel because it has been done in small samples, but mainly with rare and neuromuscular diseases previously, but this study broadened that or generalized that to a much more clinically relevant population. The clinical implications also seemed to be much greater than what has been reported by previous papers. Dr. Greg Hundley: Very nice. Listeners, we have in addition to Dr. Omland, we have another expert with us today, Dr. Chris deFilippi, really in the area of biomarkers particularly as they pertain to cardiac injury. Dr. Greg Hundley: Chris, now turning to you, how do we put the context of the results today really with the broader scope of what we have learned about cardiac troponin I and cardiac troponin T and then their use in diagnosing acute ischemic syndromes or even forecasting future cardiovascular events down the road? Dr. Christopher deFilippi: Thank you, Greg, and thank you Circulation for inviting me to participate in this podcast and to write this editorial. First, Christian, this was a terrific paper and one that was probably great to review during the pandemic because, as I spent a good Sunday peeling back layers of the onion and reiterating what Torbjorn said, this paper makes a tremendous contribution where there already was some knowledge to maybe the expression of the cardiac specific troponin T and skeletal muscle, but there's something there for everyone just to get the takeaway message, but for those who really want to delve in, there are supplemental tables that contribute a huge amount of nuance and detail that I think will help guide researchers in the future in maybe how to optimally use cardiac troponin T and troponin I both in the evaluation for acute myocardial infarction and then in a variety of chronic conditions, so first putting this in context of how you would evaluate patients with acute myocardial infarction, and that's the predominant indication for measuring a high sensitivity troponin T or troponin I. Dr. Christopher deFilippi: As Christian in an earlier study has shown and others have shown, actually, the correlation between a high sensitive troponin I by a variety of commercial assays. Troponin T is really pretty good. I think in one study from Christian's group, it was measured at 0.89. Now, the issue that's relevant is more around the edges. People who come in with just a low elevation and, as Christian pointed out and colleagues pointed out in the paper, using the ESC algorithm, a number of those patients would have qualified for myocardial infarction with the skeletal myopathies particularly the myositis or the non-inflammatory myopathy. If there is an index of suspicion for these disorders I think particularly around the cutoff for troponin T, one has to be cautious. Whether one can actually look at serial changes and try to differentiate that way I think is an open question. It may be. Dr. Christopher deFilippi: I think the other thing that gets quite interesting for me in an area that we've delved in over the past decade is the use of high sensitive troponin T or troponin I as a measure of chronic injury that's been codified in the fourth universal definition of MI published four years ago to identify individuals at risk. These can be individuals who are living in the community without known cardiovascular disease or actually without, perhaps, a lot of other comorbidities other than advanced age, for example, who an elevated troponin I or troponin I can be indicative of an increased risk for incident heart failure over the next five to 10 years. It can be patients with other chronic comorbidities. Dr. Christopher deFilippi: Actually, what drew me to this paper and thinking along these lines was a paper that Torbjorn had published back in 2013 where, using the key study which are individuals who have chronic ischemic heart disease without heart failure, he measured both troponin I and troponin T and found there was quite a discordance. There, we're looking at … value of about 0.4 and found that troponin I was a great predictor for the risk of coronary heart disease event and an acute myocardial infarction in the future, but T was not, but both T and I were good predictors of incident heart failure in the future. Dr. Christopher deFilippi: Other investigators, the … investigators, investigators from Scotland have also found this discordance between I and T in chronic ambulatory populations with or without comorbidities, and so it opens an interesting question in individuals with maybe conditions of pre-frailty or frailty or some element of sarcopenia, subclinical skeletal muscle disease. Does this cause this discordance? Ultimately, we know particularly with heart failure, with preserved ejection fraction, it is a systemic disorder, and measures of skeletal muscle disease may be relevant in ultimately determining who's going to have symptomatic heart failure. Dr. Christopher deFilippi: I think it really opens things wide open potentially to further investigation. Is this modifiable? Is it through intervention simply like physical activity? Could you see changes in cardiac troponin T that may be reflecting cardiovascular changes and skeletal muscle changes, but maybe not so much with I, and does this have relevant prognostic implications? I think I was really excited about it based on the defined pragmatic findings with respect to evaluating patients for myocardial infarction who have these underlying skeletal muscle diseases, but also implications, what this might mean in chronic disease populations as well. Dr. Greg Hundley: Very nice. Well, Chris, you've led us really to our next series of questions, and maybe we'll circle back with each of you, first, Christian. What do you see, Christian, as the next study to be performed in this space? Dr. Christian Mueller: I think the next study should address two aspects. The first one is I think we already, with the current population have found that skeletal muscle disease includes various pathologies, and as indicated by Torbjorn, the cardiac troponin T re-expression seems to be at least of our current understanding limited to the two groups of myositis and the muscular dystrophies, whereas the other skeletal muscular disorders at least in those that we have currently investigated did not seem affected. However, we were limited by the number of patients in this subgroup, and so for sure need a larger population to cover all aspects or all classifications of skeletal muscle disease in more detail. Dr. Christian Mueller: The second point that I'd like to highlight is the followup and to look for cardiac events and to look for cardiac changes, functional or anatomical changes in cardiac imaging, because it still may be that some of the T that is more commonly seen in this patient, that the majority of this is derived from the heart, so it's not a black and white, it's only from the muscle or only from the heart. It's still possible that some of the higher concentration of T found in these patients, as in many of the skeletal muscle systemic disorders, they have cardiac involvement which may not be identifiable by current imaging techniques at the first visit. This may become apparent during followup, and so these studies will help us to get a better quantitative understanding, so ideally to understand is it just a tiny amount, I don't know, 10, 20% of the systemic T concentration that is derived from the muscle? Then it would have a very different clinical implication as compared to if, I don't know, more than 50% of the systemic concentration would be derived from the skeletal muscle rather than the heart. Dr. Greg Hundley: Very nice. Torbjorn, I would like to turn to you. What do you see as the next study to be performed in this space? Torbjorn Omland: Oh, I agree with Christian that the serial assessment of changes of disease activity versus troponin changes would be very interesting to study in more detail and also correlate that to changes, for instance, by cardiac MRI if you can see whether there are actually correlations there. Long-term prognostic implications of skeletal muscle derived cardio troponin is another subject, and then, finally, I think that we do need to know even more accurately what is the impact of these alterations on the diagnostic workup in the acute coronary syndrome setting. Is it really a clinically important confounder? I think studies that could address that will be important. Dr. Greg Hundley: Very nice, and then finally Chris, and, Chris, I want to add just another question. Just from my listening to this, if I'm trying to identify someone with an acute ischemic syndrome and then they may also have an underlying skeletal muscle disorder, both Christian was talking about inflammation, but you brought in frailty and things of that nature. Should we really then turn clinically to measuring cardiac troponin I in this setting when we're trying to rule out, for example, acute myocardial infarction? Dr. Christopher deFilippi: Yeah. I don't want to overstate that. I mean, Christian's work and others have shown actually a high sensitive troponin T and a variety of different high sensitive troponin Is in a very heterogeneous chest pain population have been equivalent, looking at receiver operator curves area under the curbs, and so they're probably our people at the margins where this will make a difference, but it should be. Listeners should be reassured at this point because troponin T is a very common assay that it's still quite efficacious and accurate for the diagnosis of acute myocardial infarction from what we know, and a lot of Christian's work has identified this. Dr. Christopher deFilippi: Again, moving into the more chronic disease population outside the evaluation of acute myocardial infarction, maybe where we can use it as a differentiator, it could be helpful in some instances to look at interventions. Earlier work has shown in just small numbers of patients have been published, but patients with hypothyroidism, patients with statin-induced skeletal myopathies, the treatment of these has actually led to a decrease in high sensitive troponin I corresponding with decreases in CK, so there may be opportunities for lifestyle interventions like physical activity, and you could see that response and whether that has prognostic implications. This could be of interest for future research. Dr. Greg Hundley: Very nice. Well, listeners, what an incredible discussion today. We want to thank Dr. Christian Mueller from University Heart Center in Basel, Switzerland, Dr. Torbjorn Omland from the University of Oslo in Oslo, Norway, and also Dr. Chris deFilippi from the Inova Heart and Vascular Institute in Falls Church, Virginia, for really helping us understand that in patients... from this research, that in patients with active chronic skeletal muscle disorders, elevations in cardiac troponin T are common and may not be related to cardiac disease. These elevations were not observed in those with assessment of cardiac troponin I and, coming back to in the case of cardiac troponin T based on this wonderful biopsy work, the elevations of the troponin T appear related to re-expression of troponin T and skeletal muscle. Dr. Greg Hundley: Well, listeners, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run. Dr. Greg Hundley: This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit aha journals.org.

W ósmym odcinku opowiem o kolejnym niestandardowym zastosowaniu miodu, czy dotyk pomoże nam usłyszeć więcej oraz co wywnioskować można z badań krwi. Spróbujemy też się trochę odmłodzić i zmierzymy się z konsekwencjami burzowej pogody na Słońcu.A jeśli uznasz, że warto wspierać ten projekt to zapraszam do serwisu Patronite, każda dobrowolna wpłata od słuchaczy pozwoli mi na rozwój i doskonalenie tego podkastu, bardzo dziękuję za każde wsparcie!Zapraszam również na Facebooka, Twittera i Instagrama, każdy lajk i udostępnienie pomoże w szerszym dotarciu do słuchaczy, a to jest teraz moim głównym celem :)Źródła użyte przy tworzeniu odcinka:Natalie Huet, "Honey could be used to make powerful computer chips and cut e-waste, researchers say", https://www.euronews.com/next/2022/04/06/honey-could-be-used-to-make-powerful-computer-chips-and-cut-e-waste-researchers-sayBrandon Sueoka, Feng Zhao, "Memristive synaptic device based on a natural organic material—honey for spiking neural network in biodegradable neuromorphic systems", https://iopscience.iop.org/article/10.1088/1361-6463/ac585bJudy Siegel-Itzkovich, "Can the deaf and hard of hearing understand sound through touch?", https://www.jpost.com/business-and-innovation/tech-and-start-ups/article-703477Cieśla, K., Wolak, T., Lorens, A. et al. Effects of training and using an audio-tactile sensory substitution device on speech-in-noise understanding. Sci Rep 12, 3206 (2022). https://doi.org/10.1038/s41598-022-06855-8Linda Geddes, "New blood test predicts risk of heart attack and stroke with twice previous accuracy", https://www.theguardian.com/society/2022/apr/06/blood-test-predict-heart-attack-stroke-double-previous-accuracyStephen A. Williams, Rachel Ostroff, Michael A. Hinterberg, Josef Coresh, Christie M. Ballantyne, Kunihiro Matsushita, Christian E. Mueller, Joan Walter, Christian Jonasson, Rury R. Holman, Svati H. Shah, Naveed Sattar, Roy Taylor, Michael E. Lean, Shintaro Kato, Hiroaki Shimokawa, Yasuhiko Sakata, Kotaro Nochioka, Chirag R. Parikh, Steven G. Coca, Torbjørn Omland, Jessica Chadwick, David Astling, Yolanda Hagar, Natasha Kureshi, Kelsey Loupy, Clare Paterson, Jeremy Primus, Missy Simpson, Nelson P. Trujillo, Peter Ganz, "Stephen A. Williams, Rachel Ostroff, Michael A. Hinterberg, Josef Coresh, Christie M. Ballantyne, Kunihiro Matsushita, Christian E. Mueller, Joan Walter, Christian Jonasson, Rury R. Holman, Svati H. Shah, Naveed Sattar, Roy Taylor, Michael E. Lean, Shintaro Kato, Hiroaki Shimokawa, Yasuhiko Sakata, Kotaro Nochioka, Chirag R. Parikh, Steven G. Coca, Torbjørn Oml, Jessica Chadwick, David Astling, Yola Hagar, Natasha Kureshi, Kelsey Loupy, Clare Paterson, Jeremy Primus, Missy Simpson, Nelson P. Trujillo, Peter Ganz", https://doi.org/10.1126/scitranslmed.abj9625William Reay, "We found a genetic link between routine blood test results and mental health disorders", https://theconversation.com/we-found-a-genetic-link-between-routine-blood-test-results-and-mental-health-disorders-180677William R. Reay, Dylan J. Kiltschewskij, Michael P. Geaghan, Joshua R. Atkins, Vaughan J. Carr, Melissa J. Green, Murray J. Cairns, "Genetic estimates of correlation and causality between blood-based biomarkers and psychiatric disorders", https://doi.org/10.1126/sciadv.abj8969Nick Lavars, ""Time jump" anti-aging method gives specialized cells a 30-year refresh", https://newatlas.com/science/time-jump-anti-aging-specialized-cells-30-years/Nick Lavars, "Revolutions: The incredible potential of...

Dagens bibelskolestudenter ligger godt an til å bli morgendagens misjonærer. Men hvordan forstår de begrepet misjon? Førsteamanuensis Solveig Omland ved NLA Høgskolen har undersøkt. Blant funnene er en sterkere betoning av Guds kjærlighet og mindre vekt på behovet for syndenes tilgivelse.

With Geeta Gulati & Torbjørn Omland, Akershus University Hospital, Lørenskog - Norway Link to paper Link to editorial

In this week's edition of Circulation on the Run, Dr. Amit Khera introduces the new Social Media Editors to our Circulation listeners. Please welcome Dr. Vanessa Blumer, Dr. Pishoy Gouda, Dr. Xiaoming (Ming) Jia, Dr. Peder Langeland Myhre, and Dr. Sonia Shah to Circulation. Dr. Amit Khera: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Amit Khera, Associate Editor from UT Southwestern Medical Center in Dallas, and Digital Strategies' Editor for Circulation. And today I have the privilege of sitting in for your usual host, Dr. Carolyn Lam, and Dr. Greg Hundley. Well, two times a year, we really have a special issue, there's no print issue for Circulation in the summer and here in that holiday time. So, fortunately, we get to use this for really whatever we want to do. Dr. Amit Khera: And today we have a very special issue. A few months ago, we transitioned over from a prior social media editor team that was Jainy Savla Dan Ambinder, and Jeffrey Hsu. We were able to recruit a fantastic group of new social media editors. You probably have seen their work behind the scenes, but you've not gotten to meet them personally. So, today I have the privilege of introducing you to our new social media editors. This group of five, that's been working for several months and we get to know them a little bit. Get to hear a little bit about their perspective on social media from fellows in training, and also what they've learned so far in their few months in working with Circulation. So, I'm going to go one by one and introduce you. And first I want to introduce you to Dr. Vanessa Blumer. Vanessa, tell us a little bit about yourself. Dr. Vanessa Blumer: Thank you so much, Dr. Khera, it is such an honor to be here. And I've had so much fun the months that I've been working for Circulation, it's truly just a privilege to work alongside this talented group. So I'm Vanessa Blumer. I am originally from Caracas, Venezuela, born and raised there, did all of my medical training back home. That included medical school, a year of rural service, or rural medicine. Then I actually did residency training in Venezuela as well. It wasn't really in my plans straight away to come to the US, but a little bit due to the political situation that we all know that Venezuela's going or suffering, I decided to come to the US. Dr. Vanessa Blumer: I did residency in the University of Miami, Jackson Memorial hospital, which I loved. Stayed there for a chief year. And then after that came to Duke University to do cardiology fellowship. I'm currently a third year cardiology fellow at Duke, doing a year of research at the DCRI, which I am enjoying a lot, and will be doing heart failure next year. I will be going to Cleveland Clinic for a year of advanced heart failure. Dr. Amit Khera: Well, you've had quite a journey, Vanessa, and congratulations, I think your match was relatively recently. So, we're excited to see where your career takes you from here and appreciate your contribution so far. Now I'm going to introduce you to Pishoy Gouda. Pishoy Tell us a little bit about yourself.     Dr. Pishoy Gouda: Morning, Dr. Khera. My name is Pishoy. I have had the privilege of doing my medical trading all over the world. I was born here in Toronto and moved to Edmonton where I mostly grew up. Since then, I traveled to Galway Ireland where I spent six years to do my undergraduate medical training. Hopped over a short flight and did my Masters in Clinical Trials in the London School of Hygiene and Tropical Medicine before returning to Canada to start my residency training. Got to work with some amazing people in Calgary while I completed my internal medicine training, and then finally returned home to Edmonton where I am in the last few months of my adult cardiology training. Dr. Pishoy Gouda: Next year, I'm really excited to start my interventional cardiology training, which is going to be really exciting. Some of my interests, working with social media, wearable technology so working with this great group has been really awesome. Dr. Amit Khera: Thank you Pishoy. Obviously lots of travels from you as well, and we definitely appreciate your expertise and interest in social media and in technology. It's been very valuable. Next someone who's closer to my backyard. Ming Jia. Ming, welcome. Dr. Xiaoming (Ming) Jia: Hello from Houston, and thank you Dr. Khera. So, it's been a great opportunity to be involved as a social media editor for Circulation. So I'm a current cardiology fellow at Baylor College of medicine in Houston, Texas. Was originally born in China, and grew up in sunny Florida. I did my medical training in Florida as well, and then moved over to Houston, Texas for residency, and now wrapping up my last year in general fellowship. Next year, I'll be staying in Houston at Baylor for interventional fellowship. Then, hopefully after that career in interventional cardiology, but as well as preventional cardiology as well, I tended to actually interest in both interventional and preventional cardiology. Dr. Amit Khera: Very cool. I know you and I were talking about this right beforehand, how that nexus of the two fields and just some of your interest in a lot of the research you've done so far. So again, offering a unique and different perspective, which we appreciate so, welcome, Ming. Next, Peder Myhre. Peder, welcome. Dr. Peder Langeland Myhre: Thank you so much, Dr. Khera. This is Peder Myhre from Norway, all the way across the pond. And it's such a great honor to be part of this podcast, which I've been a big fan since it started a couple years ago and where Carolyn Lam has been doing with it, it's been really amazing. And I've actually been promoting it to everyone I know with any kind of interest in cardiology. My position in training right now is that I'm in the last year of cardiology training and I'm also doing a 50% post-doc at the University of Oslo with Professor Torbjørn Omland as a mentor. And as a part of my training, I was one year at Harvard University at Brigham Women's Hospital to do research with Professor Scott Solomon's group a couple of years ago. Dr. Amit Khera: Well, we appreciate your affinity and now you get to be on the podcast. That's pretty exciting as well. I should say, each of you is linked to an outstanding Associate Editor at your home institution. And so we're glad you have that mentorship as well there too. And speaking of someone at home institution, someone who I've known for a very long time, Dr. Sonia Shah. Sonya, introduce yourself, please.   Dr. Sonia Shah: Thank you, Dr. Khera. No, just to echo what everyone has said already, it truly has been an honor and a privilege to work with this awesome team. And it's been a lot of fun along the way. So I'm Sonia Shah. I'm a third year cardiology fellow at UT Southwestern in Dallas, Texas. Originally from Central Florida, actually. And then did my undergrad medical school training in Chicago and then went out to the West Coast for my residency training was out at Stanford and now I'm loving being in Dallas. So it's been a lot of fun. So I particularly have an interest in women's cardiovascular health and advanced imaging. And so currently looking for jobs now. Dr. Amit Khera: Well, I can say you've been a star fellow and have a really incredible and unique skillset. And, so we look forward to seeing what your career brings and certainly you've brought a lot to our podcast. And we'll talk more about that in just a bit, since you are longest standing social media editor currently. Well, I want to now dig in a little bit and you all again, I want to thank you for what you've done for the last several months. I certainly have learned a lot from you. We've had some discussions as a group about, thoughts about social media and how social media works. Dr. Amit Khera: And so maybe we'll start with the sort of existential question about, why social media? What is the value for journals, if you think about Circulation, but really any journal. What does social media bring? And again, you all have a unique perspective as largely fellows in training and Vanessa, maybe I'll go back to you a little bit about, why social media? What's the point of relevance about all this work that you're doing? Dr. Vanessa Blumer: Yeah. Thank you so much, Dr. Khera. I think that's a great question. And I do think that that's a question that we ask ourselves every day as we're doing this. I think the way that the medical literature has been evolving, it's been evolving in a way of social media and people are consuming more and more social media daily. I think in my own daily life, I discover articles that I'm interested in through social media a lot more than I used to before. And I also discover that I'm interested in particular articles, the way that they are transmitted in social media or the way that they're presented in social media. Dr. Vanessa Blumer: So I think we're reinventing ourselves and reinventing the way that we present to the public, the articles that we have in Circulation, so that people want to read our articles or want to read the articles that authors are doing such a great job at putting together. So I think, we are coming up with creative ideas every day and it's part of what we discuss as a group of how do we present this so that people want to read the articles and discover all the hard work that authors are putting together through different social media platforms. Because we know that people consume not just one social media platform, but several. So I think there's huge potential in social media if we use it in the right way. Dr. Amit Khera: Yeah. I think your points well taken. I know we're going to talk a lot about Twitter today, but as you pointed out, there are other media as well. That's just in the sort of main, I guess, currency and in the medical and cardiovascular literature. And you mentioned value to authors and one thing you mentioned, which I'll transition a little is about the way things are presented, help you get interested in them. And so that gets to the art of the tweet. Something we've talked about a little bit and, there's a little bit of on the job training, if you will. And we've talked about is there a gold standard in terms of what makes a good frankly, a medical journal tweet. Well, Ming, what do you think? You've been toiling over this for a few months now and tell us what you think is helpful in a medical journal tweet in terms of achieving the goals that Vanessa mentioned. Getting an audience interested in reading these articles is really doing justice for the authors to transmit their research. Dr. Xiaoming (Ming) Jia: Great question, Dr. Khera, and this is something that, as a social media editor, I'm still learning. So for me, writing a concise tweet is very important. Trying to get that essence of a entire study into a very limited number of characters. Obviously having a great figure that highlights the key findings of a study is also very important as well. Now at the same time, I think the most effective posts though, are those that serve as a hook for the paper. So, while we want are tweet to stand on their own. I think the most effective tweets helped to entice the audience to want to read a little bit more and go and read the entire manuscript. So certainly there is a art and skillset in terms of writing these effective posts. Dr. Amit Khera: Yeah. You certainly bring up some key points, right? So being concise, one by definition and but two is, there are tweets that sometimes can go on and on and that comes into using some interesting hashtags and some shortcuts. But I think your point about innuendo, enticing, not giving away the whole story, but just enough to get people to want to read more. And I think that that is an art. Dr. Amit Khera: And I've certainly seen as you all have done this more and more about how your own writing and tweets have evolved. Pishoy, we've talked a little bit about, all of you are researchers, you've all done some great research, about thinking about social media, sort of a research area. Again, since there's no gold standard about what's a great tweet, just thinking about it more of a discipline as we do any other area that we want to explore scientifically. What are your thoughts about, how do we figure out more, learn more about what makes a great tweet? Dr. Pishoy Gouda: Yeah. Evidence based tweeting is something that I've been interested in. Everything that we do, we want to make sure that we do it well and that we do it effectively and the same goes with social media posts. So what works, what raises interactions with our content. And that's something that other disciplines and advertising have been doing all the time and we should be doing the same as well. If our goal is to increase interactions with our content, then we want to make sure that we are doing it in the most evidence based way. And we've learned a few things. We know that cardiologists and individuals in medicine in general have been using Twitter much more frequently as a way to consume in both your medical and research content. Dr. Pishoy Gouda: So what makes a post great and what increases its interaction and the bottom line is we don't really know. We have a few studies and a few small randomized controlled trials that have been done that give us some insight. We know that vigor, that tweets that include images might pull readers to them a little bit more. But you know what exactly works. We have a lot of observational data, but we don't have a lot of high quality data that gives us the answer to this question. So what we've learned so far is use images, use links. If you can use graphical abstracts, that seems to help as well. But, it's something that we're continuously looking at and we're really excited to put together some new evidence coming up soon in the future. Dr. Amit Khera: Evidence based tweeting. I like it. As you and I have discussed, my predecessor Carolyn Fox had a randomized trail called Intention-to-Tweet using Circulation and then a follow-up study to that. So we hope to do also some good high quality research about social media and what works. Well, that gets to who's your audience, right? I always like to think about when you start something, who's your audience. And there could be lots of people. I think probably our strike zone is researchers, scientists, clinicians, of course, there's lots of lay individuals too, that are paying attention on social media. One thing that's different about Circulation than some other journals is this melding of basic science and clinical science. Some journals are all basic science and all clinical science and Circulation's both. Dr. Amit Khera: And I mean, frankly, that's posed an interesting challenge for this group. None of you are, including myself, are card carrying basic scientists, if you will. So we've had to translate those articles. And I would consider that both a challenge, but also an opportunity because, if we're speaking to a basic science audience, of course we may have one tone we use, but we want this basic science. I think that's the purpose of Circulation is basic science applicable to the clinician and clinical researchers. So, translating that's been a real opportunity. And Peta, maybe I can ask you about that opportunity of translating basic science for clinical researchers and clinicians. Dr. Peder Langeland Myhre: Yes. I completely agree. And I've learned so much from this job as a social media editor to really try to get the essence out of a basic science paper and the translational outlook for clinicians. Because all of the papers that are basic science that at least I came across in Circulation also have a clinical implication and a translational side of it. And I think when we read these papers and try to sum it up in one tweet, we want to keep the most important essentials of the basic science, but also extend it to clinicians so that they understand in what setting and what this can potentially mean in the future. So for me, that's the biggest challenge when we review basic science papers, but it's also perhaps the part of this job that I learn the most. Dr. Amit Khera: Yeah. I agree. I think we're all learning a lot. I've certainly learned a lot by delving in deeper into the basic science papers and figuring out how to translate them appropriately. And I think this really highlights, as you mentioned, what Dr. Hill our Editor in Chief, his feeling is basic science papers in Circulation all have to have important clinical implications. That's the benchmark, if you will. So I think we've seen that shew in terms of what papers have come across for you all. Dr. Amit Khera: Well, I'm looking now at our longest standing social media editor, Sonya Shaw, she started a few months before as sort of a transition because we certainly wanted someone in place that could help bridge between the old and the new. And Sonya, you've had a decent amount of experience now with two editorial teams. Tell us what you've learned so far by working as a social media editor at Circulation. What are some of the observations you've had and some of the things you've learned in this space? Dr. Sonia Shah: Yeah, certainly. So I think a couple things. I think my ability to accurately and concisely convey the important key points from each journal has definitely improved. But I think the other unique thing, unique perspective that we gain as social media editors is getting to actually see the behind the scenes workings of how the journal works and how papers are put together and accepted. And so I think it's been interesting to see how papers are being analyzed and the teamwork that's required by the Associate Editors and the Editors and making sure to do each paper justice and properly evaluate it. So I think that's been a really cool experience. It certainly has improved my ability to write when I try to think of, what are the key points I want to include. And how to convey information in a way that will be appealing to journals. Dr. Amit Khera: Well, thank you for that. We take this job very seriously, as you all have in that point about doing each paper justice, because you've seen, one, from the author's perspective about how much work they put in and you've been an author before and want to make sure that we appropriately appreciate that. And then also the Associate Editors, there are hours and hours of work for each paper. So even though it comes out, maybe in a few characters in a tweet, we appreciate all that's going behind it. And I'm glad you've gotten to see that process through. Ming, maybe I can come back to you. What have you learned so far by working in Circulation for the last few months? Dr. Xiaoming (Ming) Jia: I do want to echo what Sonya just said in terms of really getting a glimpse of the behind the scenes work is quite amazing. The amount of work and coordination it takes to get a paper from publication to promotion. And, we don't really get that exposure as a author for a manuscript or even as a peer reviewer. So, that part has definitely been a great learning experience. On the other side, I do find it interesting that ever since taking on this role as a social media editor, my way of writing has changed as well. So, trying to be more efficient, getting key points across and really being concise and focused in my manuscript writing. So that's been very helpful from a personal level as well. Dr. Amit Khera: We're very thankful for that. I think we always want this to be bidirectional where you all are contributing in meaningful ways. But that the goal here with fellows in training in this role, social media editors. But for you all to be learning something as well. So I'm glad that that has occurred. And we'll talk more about that in just a few minutes. Dr. Amit Khera: Well, we have a couple of international social media editors and this is my intention. We want to make sure we have a diverse group of social media editors. By background, by thought, by location. And, one way that the beauty of that is again, we get different perspectives. I guess the downside is time zones. We were just joking before, as we were starting this podcast about some of us are very early in the morning and one of our social media editors unfortunately is always late at night when we have our meetings. Peta, tell us a bit about unique observations from an international perspective. You said you've been following Circ for a while, but tell us, from your perspective in Europe, the social media process and how you see it. Dr. Peder Langeland Myhre: Thank you so much. And it's actually been a really transformation for me from before I spent my year in Boston to after. Because I really learned the potential of using social media and especially Twitter to stay updated and get the latest papers and thoughts from experts in the field. And I remember before I went there, I was often very frustrated that it was so inconvenient to get across important papers that was within my field of interest. Because all the journals were not longer sent in paper to our hospital and the websites were confusing. Dr. Peder Langeland Myhre: So when Dr. Vaduganathan at the Brigham & Women's Hospital introduced me to Twitter, that really was an eye opener for me. And, ever since that, 90% of the papers that I read I first see on Twitter. Because that's the first place, the people that are within my field, publish it or tweet it. And also I'm able to, you follow a certain amount of scientists and physicians and they have the same interest as you. So it's also, most of it is relevant for what I want to read. So it's really been a revolution for me to start to use Twitter and social media for medical and scientific purposes. And not only for friends and family. Dr. Amit Khera: Yeah. I think it's some great points. One, is even simplistically just be able to access articles, which we don't always appreciate, from people from around the world. And then obviously what many can, is follow people that have similar interests and amazing to see sort of how different people consume the literature. And for you Twitter being your entry point, I guess, for how you do that, which is I'm sure many, many people do the same. And we have another international editor you met earlier. Pishoy, tell us your perspective. And obviously you're in Canada now and have moved many places. What's your perspective from an international perspective, looking at social media? Dr. Pishoy Gouda: Coming to work at Circulation, I expected a very niche editorial board, but what I'm really finding out is boy, does it take a village. And it is people from all over the world. And it really hits home that collaboration and research has become a global phenomenon. And to be able to do art well and to appropriately represent researchers from across the world. We have an editorial board and team that is global and it really does take a village to take a paper from submission all the way through the publication team, starting from the authors to the peer reviewers, editors. But then the entire post-production team, which is behind the scenes and don't get a lot of glory, but they do a lot of the heavy lifting to make sure that, the research that's submitted gets in front of readers. And that's something that I hadn't really thought of before. And it's been really interesting to see how that process unfolds. So that's definitely been eye opening for me. Dr. Amit Khera: Well, I appreciate what you said about, when it takes a village and I would be remiss if I don't always call out Augie Rivera, who is the engine and mastermind behind Circulation, who's helping us do this podcast today and every week. But the other part is the international workings I think many may not appreciate. We have editorial board meetings every other week at very different time zones on purpose because we have people in Europe and in Asia and in Africa. And as you know, Dr. Lam who's the main podcast editor is in Singapore. Dr. Amit Khera: So, this is by intention. It really gives us a wonderful international perspective. And so we're so glad to have you two as part of our international team. Well, I think that's a great transition, a little bit to just talking about fellows in training and involvement in journals for Circulation perspective, and from the AHA, I should say, getting fellows in training involved in cardiovascular research, the editorial process, this is something that's really important to us and something we continually strive to find new ways to do. So, Vanessa, I'm going to come back to you. I know, not just at Circulation, but I know at other journals you've had some responsibilities. Tell us a little bit of what you tell other fellows in training about getting involved in journal activities. How to, and what's the benefit. Dr. Vanessa Blumer: Thank you so much Dr. Khera. I think this is such an important question. First my recommendation is, get involved in one way or another. I think there's different ways of getting involved as simple as just start reviewing articles. And the reason I say this is as I aspire to become an academic, a well-rounded academic cardiologist, I think my involvement with journals has just made me a much better researcher, a much better academic cardiologist. It's made me, I think, Sonya said this so well, it's made her a better author. It's made me a better writer. So I think it compliments what you do just so much better. I think you're better at what you do when you see the behind the scenes and you understand what happens in scholarly publishing. So I think there's different ways of getting involved. I know that Circulation has many and then probably a good way is to reach out. Dr. Vanessa Blumer: I know that people can reach out to us and we can probably guide them along the way, but different journals have different ways of getting involved. But I think if you want to start, one way is start reviewing. You learn a lot through the review process in itself on how an article is structured. And there's some journal that have a little bit more of a mentorship approach towards reviewing. And, that's also a good way starting out. When we start off as residents, we get some papers get in our inbox to review and we really don't necessarily know how to approach it. So maybe a mentorship approach to it is a good way to start. But overall, I would just say, start getting involved. I think it's a great experience. Personally, I have learned so much from it and I think I'm just a better academic cardiologist because of it. Dr. Amit Khera: Thank you for that. And I think your point about just find ways to get involved. And I think our challenge is to continue to facilitate ways for trainees, fellows in training and others to get involved. But I think that that first step in finding maybe a mentor of your institution that could help guide you would be important. And I'm going to finish with Sonya. I'm going to come back to you. You've not only had the social media editor window for quite some time. Being at Circulation, you get to see behind the curtain perhaps more than others because, Circulation is such a big part of what we do at UT Southwestern. And, we've had this Fellow Reviewer Program where you've been able to participate in reviews and things like that. From your perspective, maybe telling the fellows in training, listening out there about getting involved in journal activities, the value that you've seen and how to do so. Dr. Sonia Shah: Yeah, I think that's a really important question. At the end of the day, the ability to read and interpret and take away the major conclusions and properly interpret a study is a skill. And so I think the more you do it, certainly the better you get at it. And being part of a journal being on the reviewer end, being on the end where you're creating social media posts is really an opportunity to develop and refine that skill. And so to all the fellows out there who are interested, regardless of whether you want to do academic cardiology or not, it is an important skill, even in the future, to be able to read and properly interpret studies. So I highly recommend it. I find for me, I've definitely learned a lot through the process and have certainly improved. Dr. Amit Khera: Well, there you have it, our five social media editors. First, I want to thank you all for your contributions to Circulation. You're an incredibly bright group as everyone learned about. I have future leaders in cardiology. And we're very fortunate to have you contributing to Circulation and to our authors and readers. So thankful to have you as part of Circulation and look forward to working with you and innovating and coming up with some creative, new ways to think about social media and ways to transmit research for journal. Dr. Amit Khera: Well, I think there you have it. Again, I'm Amit Khera. I'm associate editor and standing in this week for Carolyn Lam and Greg Huntley, who will join you again next week. So thank you for joining us for Circulation on the Run. Dr. Greg Hundley: This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.

Today's guest is a magical mermaid maiden that I am honored to call cofounder of pstprtm Anne Omland. We met through our other cofounder Blair Badenhop and immediately sparks flew. We are so aligned and so different and seriously, she has mermaid hair. Today we are talking about losing your shit as a mom and trying to find it again. And I urge you to listen until the end. Her definition of motherhood is...beyond. Anne is a co-founder and CXO of pstprtm, a media company and community space on a mission to revolutionize the postpartum experience. She's a Yoga & Meditation Teacher, Hypnobirthing Childbirth Educator, Women's Health Coach, Doula-in-training and the master of creating sacred, healing experiences for mamas and mamas to be. In her other business Mamakind, she creates personalized wellness plans that care for the whole woman on her journey to motherhood, bridging the gaps from standard care. Learn more about Anne at www.mamakind.co and follow her on instagram @wearemamakind   Download your free guide to the 20 Things No One Tells You About Pregnancy & Postpartum here. Want to connect with me further? Follow me on instagram and join our private Facebook community Mom's Club.  Want to learn more about what I do and why I do it? Are you looking to elevate your pregnancy and postpartum experience? Visit me www.alissa-alter.com

This week's episode features author Kieran Docherty and Associate Editor Torbjørn Omland as they discuss the article "The Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients with Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts: I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate, editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, we've got an exciting feature this week involving Neprilysin license inhibition and left ventricular remodeling in patients with asymptomatic left ventricular systolic function after they've sustained myocardial infarction. But before we get to that feature discussion, how about we grab a cup of coffee and jump in on some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I'd love to, and I want to talk about transcatheter aortic valve replacement, or TAVR, that we all know is really transforming our management of aortic stenosis. Despite rapid improvements, however, serious complications remain relatively common and are not well-described by single outcome measures. So the purpose of this paper was to determine if there was site-level variation in TAVR outcomes in the United States using a novel 30-day composite measure. And this is from Dr. Desai and colleagues from Hospital of University of Pennsylvania. So they performed a retrospective cohort study using data from the STS/ACC TVT registry to develop a novel-ranked competent performance measure that incorporates mortality and serious complications. Based on the associations with one-year risk adjusted mortality and health status, they identified for peri-procedural complications to include in the composite risk model, in addition to mortality. And ranked empirically, according to severity, these were: stroke, major life-threatening or disabling bleeding, stage three acute kidney injury, and moderate or severe perivalvular regurgitation. Dr. Carolyn Lam: Now, based on these ranked outcomes, they found that there was significant site-level variation in quality of care in TAVR in the United States. Overall, better-than-expected site performance was observed in 8% of sites, whereas performance as-expected was observed in 80%, and worse-than-expected performance was observed in 11% of sites. Dr. Greg Hundley: Carolyn, really interesting comprehensive data. So how do we put this all together? And what's the take-home message for us, clinically? Dr. Carolyn Lam: Well, there are substantial variations in the quality of TAVR care received in the United States, and 11% of sites were identified as providing care below the average level of performance. Further study is necessary to determine the structural, process-related, and technical factors associated with high- and low-performing sites. And all this is discussed in a beautifully, beautiful accompanying editorial by Drs. Dharam Kumbhani and Eric Peterson.   Dr. Greg Hundley: Oh, fantastic. You know, Carolyn, those editorials are so helpful in helping us put these new data in perspective. Well, my next paper comes to us from the world of preclinical science, and it's from Professor Vincent Christoffels from Amsterdam in UMC. So genetic variants of SCN10A, encoding the neural voltage-gated sodium channel NaV1.8 are strongly associated with atrial fibrillation, Brugada syndrome, cardiac conduction velocities, and heart rate. And these investigators studied the cardiac expression of SCN10A and the function of a variant-sensitive intronic enhancer previously linked to the regulation of SCN5A, and coding the major essential cardiac sodium channel NaV1.5. Dr. Carolyn Lam: Wow, great. So what did they find, Greg? Sounds like a first-of-its-kind study. Dr. Greg Hundley: Right, Carolyn. So genetic variants in and around SCN10A modulate enhancer function and expression of the cardiac-specific NCN10A short transcript, and the authors propose that non-encoding genetic variation modulates transcriptional regulation of a functional C-terminal portion of NaV .8 and cardiomyocytes that impacts NaV1.5 function, cardiac conduction velocities, and arrhythmia susceptibility. Dr. Carolyn Lam: Wow, that was a lot. So what are the implications, Greg? Could you simplify it for us? Dr. Greg Hundley: Yes. Right, Carolyn. So three things. First, the authors uncovered a novel alternative mechanism for how the SCN10A locus regulates cardiac conduction. Second, their data implicate that genetic variation-sensitive regulation of expression of NCN10A short modulates conductivity of the heart, and can predispose to arrhythmia in the human population. And then finally, Carolyn, in deciphering the underlying mechanism of the increased NaV1.5 mediated current density by NaV1.8 short, the authors believe their findings could ultimately lead to the development of novel therapeutic strategies for particular conduction disorder. Dr. Carolyn Lam: Thanks, Greg. Well, this next paper is really interesting. It's the first validation of the enhanced potency of human-induced pluripotent stem cells-derived cardiomyocytes over-expressing Cyclin D2, or CCND2, under the control of myosin heavy chain promoter, and differentiated into cardiomyocytes. Now, that was a mouthful, but so interesting, because Dr. Zhang and colleagues from University of Alabama in Birmingham used infarcted pig hearts, and transplanted these amazing cardiomyocytes, and found that they were associated with proliferation of recipient heart cardiomyocytes, epithelial cells, and smooth muscle cells, all, at least partly, by paracrine activity. Dr. Greg Hundley: Well, Carolyn. Really an involved clinical design. So, what are the clinical implications of all this research?   Dr. Carolyn Lam: Well, first, I think the paper validated a novel therapeutic strategy aimed at upregulating proliferation of recipient cardiac cells using human-induced pluripotent stem cells-derived cell or cell products. Furthermore, targeting the myocyte cell cycle regulators, such as Cyclin D2, holds a strategic potential for re-muscularization of an infarcted region. Dr. Greg Hundley: Very good, Carolyn. Well, how about we see what else is in this issue? So I'll start first. There's a Research Letter by Professor Marston, entitled 'Combining High-Sensitivity Troponin with the American Heart Association/American College of Cardiology Cholesterol Guidelines to Guide of Avelumab Therapy'. Next, there's an ECG challenge from Dr. Feliciano, entitled 'An Ominous EKG'. And then finally, there's a very nice exchange of letters from Drs. Lang and Sattar regarding a prior publication: volume status is the key in heart failure. Dr. Carolyn Lam: And finally, a very important perspective piece by Dr. Catapano on omega-3 for cardiovascular disease: where do we stand after reduce it in strength? Wow, that was great, Greg. But let's move on now to our feature discussion. Dr. Greg Hundley: You bet. Dr. Greg Hundley: Well, listeners, we are on to our feature discussion today, on this July 20 issue. And we're very excited to have with us Dr. Kieran Docherty from University of Glasgow in Glasgow, Scotland, and our own associate editor, Dr. Torbjørn Omland from University of Oslo in Oslo, Norway. Welcome, gentlemen. And Kieran, let's start with you. Could you describe some of the background related to your study, and what was the hypothesis that you wanted to address? Dr. Kieran Docherty: Well, firstly, thank you very much for the invitation to discuss our trial today on the podcast. The background of our trial was that we are all aware that the development of left ventricular systolic dysfunction following acute myocardial infarction places patients at a subsequent increased risk of the development of heart failure, and the process of progressive dilatation of the left ventricle and a reduction in stroke volume, known as adverse left ventricular remodeling, is the process which underlies this elevated risk of heart failure. And many of the treatments that have been shown to be beneficial following myocardial infarction, such as [inaudible 00:09:24] , and angiotensin receptor blockers and beta blockers, the benefit of these medications, in part, is due to their ability to attenuate this process of adverse remodeling. Now, our hypothesis was that it would be possible to further attenuate, prevent, or delay the process of adverse remodeling in patients at risk of heart failure following myocardial infarction, by the addition of a Neprilysin inhibitor to current standard of care. Dr. Kieran Docherty: Now, as we all know, a Neprilysin inhibitor in the form of sacubitril valsartan when combined with an angiotensin receptor blocker, has been shown to improve outcomes in patients with symptomatic heart failure, with reduced ejection fraction in the PARADIGM-HF trial, and Neprilysin inhibitors increase endogenous levels of natriuretic peptides, amongst a range of other substrates for Neprilysin, including adrenomedullan, GLP-1, and bradykinin. And our hypothesis was that adding in a Neprilysin inhibitor, thereby increasing endogenous levels of these peptides with potentially beneficial effects, such as reducing fibrosis, reducing hypertrophy, [inaudible 00:10:34] and diuresis, may have an additive beneficial effect on left ventricular remodeling in these high-risk patients with left ventricular systolic dysfunction following myocardial infarction. Dr. Greg Hundley: Very nice hypothesis. So, how did you set up, Kieran, your study design, and what study population, how many patients and whatnot, did you include in your study? Dr. Kieran Docherty: Well, the first consideration when designing the study was broadly, what group of patients should we involve? And the main limitation was the indication for the use of sacubitril valsartan in patients with symptomatic heart failure, so we did not feel that we could include these patients. Therefore, our study population included patients who had asymptomatic left ventricular systolic dysfunction following previous myocardial infarction. And specifically, we wanted patients who were at least three months following my cardiac infarction. And the reason for that was to try and exclude patients who had transient systolic dysfunction or left ventricular stunning. And we performed a screening transthoracic echo at this time point. And if patients had an ejection fraction of 40% or less on echo, and if they were tolerant of a minimum dose of an ACE inhibitor, 2.5 milligrams of ramipril BD or equivalent, and they were taking a beta blocker, unless contraindicated or not tolerated, then they were suitable for randomization. Dr. Greg Hundley: Very good. And what did you find? Dr. Kieran Docherty: So we find that in comparison with the ARB Valsartan, sacubitril valsartan did not have any beneficial effects on cardiac MRI-based measures of left ventricular remodeling. And the primary end point of our study was left ventricular end systolic volume index. There was also no improvements in biomarkers of myocardial stress, i.e. NT-proBNP, or my cardio injury, i.e. high sensitivity to Troponin I. Dr. Greg Hundley: Very nice. And any pertinent issues relevant to, perhaps, some subgroups, regardless of age or perhaps gender? Dr. Kieran Docherty: So in a post-hoc analysis, we performed an analysis of the primary endpoint in patients who were below or at or above the median NT-proBNP level, which is 238 p-grams per mil. And we found, very interestingly, the suggestion of a benefit, in terms of left ventricular remodeling with a reduction and systolic volume index in patients who had higher levels of NT-proBNP compared to those who had lower levels. Dr. Greg Hundley: Very good. Well, listeners, let's turn now to our associate editor, Dr. Torbjørn Omland, who... Torbjørn, you see many papers come across your desk. What attracted you to this manuscript? And then how do you put the results of this study in the context with other studies that have been published, particularly recently, in patients with heart failure that have received sacubitril valsartan? Dr. Torbjørn Omland: So, Greg, there were many aspects of this trial that made it very attractive for circulation. I think the hypothesis was very interesting, and also it is a very well-conducted study using the reference methods for assessing left ventricular function, using that for assessing the primary endpoint. And they also have a broad array of secondary end points that also sort of provide insight in potential pathways or mechanisms that can explain the effect sacubitril Valsartan. So, that's also a very sort of hot topic within the cardiology research currently, and we know that the ACC, actually a much larger study, PARADISE-MI, was presented. And we knew that this study was also very interesting, because we knew when we received this manuscript, that another, bigger trial that's sort of related would be presented at the ACC at the late-breaking clinical trial sessions there the PARADISE-MI study. But this sort of provided insight that nicely complimented the results of that study. Dr. Torbjørn Omland: And I think as Kieran alluded to, we already have the very impressive results from PARADIGM-HF is showing a very substantial benefit in patients with chronic heart failure and reduced ejection fraction. And then we have sort of the borderline results from the Paragon trial, in those with preserved ejection fraction, where it actually was a gradient from those with mildly elevated, where there seemed to be a beneficial effect to those with more normal EF, where there was no effect. So, this study sort of provided new information, very relevant to the whole field, I think. Dr. Greg Hundley: Very nice. Well, gentlemen, I want to turn back to you and ask each of you, first Kieran, and then Torbjørn. Kieran, what do you think is the next study that needs to be performed in, really, this sphere of research? Dr. Kieran Docherty: As Torbjørn has already alluded to, PARADISE-MI kind of... It fills the gap across the spectrum of heart failure. So in patients who are at high risk of heart failure immediately following myocardial infarction, that that group of patients were studied in PARADISE-MI. And there is an echocardiographic sub-study of PARADISE-MI, which we await the results for. And I think that will be very interesting, because our patient population was distinct from the group studied in PARADISE-MI, namely the fact that the median time from MI was 3.6 years. So, these patients were not in the throes of the neural humoral activation at the time of acute myocardial infarction and prior to the development of established my cardio scar and fibrosis. And so, it may be that the addition of a Neprilysin inhibitor to patients immediately following myocardial infarction may have some benefits, in terms of attenuating or preventing ventricular dilatation reduction and injection fraction that is observed. So I think we await the echocardiographic results of PARADISE-MI with great interest. Dr. Greg Hundley: Very good. And Torbjørn , do you have anything to add? Dr. Kieran Docherty: Yes. I found observations that actually, in terminal proBNP measurements, could potentially identify a higher-risk group that actually could benefit from the intervention. It was very interesting. So I think we always speak about precision medicine and cardiology, and I think this is sort of one avenue that we should pursue and see whether we use biomarkers like NT-proBNP to identify those patients who will benefit most from interventions like sacubitril Valsartan Dr. Greg Hundley: Excellent. Well, listeners, we've heard a really interesting discussion today. Another study investigating Neprilysin inhibition in combination with angiotensin receptor blockers, and basically highlighting that in patients with asymptomatic left ventricular dysfunction following several years after myocardial infarction, that treatment with sacubitril Valsartan did not have a significant reverse remodeling effect just compared with valsartan alone. Well, on behalf of Carolyn and myself, we want to thank Dr. Kieran Docherty and his submission here to circulation, and also our own associate editor, Dr. Torbjørn Omland. Dr. Greg Hundley: And for all of you, we wish you a great week, and we hope to catch you next week on The Run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.  

First join author Marc Dweck and Associate Editor Victoria Delgado as they discuss the article "Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial." Then, join authors Torbjørn Omland and Geeta Gulati as they discuss the article "Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) Extended Follow-Up of a 2×2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol." Dr. Carolyn Lam: Welcome to Circulation On The Run. Your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Hooray, it's another double feature week! And guess what, these two papers are two randomized control trials. One looking at progression of aortic stenosis and the other, looking at a prevention of cardiac dysfunction following adjuvant breast cancer therapies. Dr. Carolyn Lam: So, very interesting two papers coming right up. But Greg, why don't you start by highlighting some of your favorite papers from today's issue. Dr. Greg Hundley: You bet Carolyn. Dr. Greg Hundley: So my first study was conducted by Dr. Gabriela Trifan and colleagues from University of Illinois who performed a meta analysis of major studies that compare the efficacy and safety of dual anti-platelet therapy versus monotherapy for secondary prevention of recurrent stroke or transient ischemic attack in those previously experiencing minor non cardioembolic stroke. And their primary outcomes were stroke and the composite of stroke, TIA, acute coronary syndrome and death of all cause. And the safety outcome was major hemorrhage. Dr. Carolyn Lam: Oh, okay. Very important study. What did they find? Dr. Greg Hundley: Right Carolyn. So the analysis included 27,358 patients. And compared with monotherapy, dual anti-platelet therapy reduced the risk of recurrent stroke and the composite outcome, but increased the risk of major bleeding. And in subgroup analysis at less than or equal to 30 days, dual anti-platelet therapy increased the risk of hemorrhage relative to monotherapy. In sensitivity analyses, the risk for hemorrhage with less than or equal to 30 days of dual anti-platelet therapy, after excluding the combination of aspirin plus Ticagrelor, was comparable to monotherapy. However, the risk of stroke recurrence and composite outcomes in the subgroup and sensitivity analyses remained decreased compared to monotherapy. Dr. Greg Hundley: And so Carolyn, the take-home message from this paper is that dual anti-platelet therapy decreases the risk of recurrent stroke and composite events compared with monotherapy. But, dual anti-platelet therapy increases the risk of major hemorrhage, except if the treatment is limited to 30 days and does not include the combination of aspirin plus Ticagrelor. Dr. Carolyn Lam: Ah, thanks for that last take home message. Thank you. Dr. Carolyn Lam: Well, the paper I'm going to tell you about is the first to examine the role of epicardial fat derived extracellular vesicles in the pathogenesis of atrial fibrillation. And this comes from Dr. Leor from Sheba Medical Center, Tel Aviv University in Israel and his colleagues who collected epicardial fat specimens from patients with and without atrial fibrillation during elective heart surgery. Dr. Carolyn Lam: Epicardial fat samples were grown as organ cultures and the culture medium was collected every two days. And the authors then isolated and purify these epicardial fat extracellular vesicles from the culture medium. Dr. Carolyn Lam: They found that epicardial fat extracellular vesicles of patients with atrial fibrillation had unique pro-inflammatory, profibrotic and proarrhythmic properties. Epicardial fat extracellular vesicles could in fact induce cellular, molecular and electrophysiological remodeling that could result in atrial fibrosis, myopathy and the development of atrial fibrillation. Dr. Greg Hundley: Wow Carolyn, so what are the clinical implications of epicardial fat extracellular vesicles? Dr. Carolyn Lam: Hmm, good question. Well, understanding their role in the pathogenesis of atrial fibrillation may for one lead to the discovery of new diagnostic markers or new targets for the prevention and treatment of atrial fibrillation. And that combined pro-inflammatory profibrotic and proarrhythmic effects of these epicardial fat and extracellular vesicles may in fact be relevant to the pathogenesis of other cardiovascular diseases associated with obesity and abnormal adipose tissue deposition. Dr. Greg Hundley: Very nice Carolyn. Dr. Greg Hundley: My next paper comes again to us from the world of preclinical science and these authors led by Dr. Masanori Aikawa from Harvard Medical School applied a systems approach in mouse experiments to discovering therapeutic targets for vein graft failure. They use global proteomics and high dimensional clustering on multiple vein graft tissues to identify potential pathogenic mechanisms. And experiments were conducted in both in vivo mouse models and in vitro human macrophages. Dr. Carolyn Lam: Oh wow. So what did they find? Dr. Greg Hundley: So Carolyn, peroxisomes proliferator activated receptors or PPAR alpha agonism by pemafibrate retarded the development and inflammation of vein graft lesions in mice, while gene silencing worsened plaque formation. Pemafibrate also suppressed arteriovenous fistula lesion development. Dr. Greg Hundley: Now, metabolomics, lipidomics, functional metabolic assays and single cell analysis of cultured human macrophages revealed that PPAR alpha modulates macrophage glycolosis, citrate metabolism, mitochondrial membrane sphingolipid metabolism and heterogeneity. Dr. Carolyn Lam: Okay. So what is the take home message Greg? Dr. Greg Hundley: Right Carolyn, thought you would ask me that. Dr. Greg Hundley: So PPAR alpha activation suppresses the development of vein graft and arterial venous fistula lesions. And PPAR alpha reduces macrophage activation by influencing macrophage heterogeneity, mitochondrial integrity, and the metabolome. So Carolyn, given that peripheral arterial disease and chronic kidney disease prevalences are increasing, warranting needs for more vein grafts and arterial venous fistulas, this target discovery platform is applicable to investigating therapies for these diseases. Dr. Greg Hundley: And a really nice accompanying editorial is provided by doctors Reilly and Bornfeldt. Dr. Greg Hundley: Well Carolyn, how about we turn to look at what is in the mailbag this week? Dr. Carolyn Lam: Well let me tell you about it Greg. We've got a cardiovascular case series by Dr. Borlaug on things are not always as they seem, multimodality exercise assessment and evaluation of dyspnea. In cardiology news by Kuhn there's a discussion of Evinecumab approval adds a new option for homozygous familial hypercholesterolemia with a hefty price tag. A perspective piece by Dr. Watkins on time to think differently about sarcomere negative hypertrophic cardiomyopathy. And finally a research letter by Dr. Ahn on reduction in Kawasaki disease after non-pharmaceutical interventions in the COVID-19 era, a nationwide observational study in Korea. Dr. Carolyn Lam: Wow. That wraps it up for the summaries. Let's go on to the feature discussions shall we, Greg? Dr. Greg Hundley: You bet. Dr. Carolyn Lam: We are about to talk about the extended follow-up results of the PRADA trial. Oh, so interesting. So happy to have with us today, doctors Geeta Gulati and Dr. Torbjørn Omland, both from the Akershus University hospital in Norway, and you would probably recognize that Dr. Torbjørn Omland is also one of our associate editors, but both here are the co-corresponding authors of this beautiful paper. Dr. Carolyn Lam: Thank you so much for coming here today. Torbjørn, maybe you could start with what is the PRADA trial? Why did you decide to do an extended follow-up? Dr. Torbjørn Omland: Yeah so PRADA was a two times two factorial randomized double blind clinical trial that sought to evaluate the effects of intervention with receptor blocker Candesartan. And a beta blocker Metoprolol in patients with early breast cancer who received anthracycline therapy as part of their chemotherapy. And then we wanted to assess the effect of this sort of preventative therapy, left ventricular function and injury. Dr. Torbjørn Omland: So we reported the primary results of the trial a few years ago and showed that intervention with Candesartan most associated with a significant elevation of the reduction in left ventricular ejection fraction that these patients may experience, and also that treatment with the beta blocker Metoprolol was associated with an intimation of the increase in cardio proponents suggesting a beneficial effect on myocardial injury. However, whether these results were or these effects were sustained after termination of the study drugs was unknown. And that was what we really wanted to address with extended follow-up study. Dr. Carolyn Lam: Yeah, makes a lot of sense, especially because these injuries I suppose could still continue. And just to be very clear, the medications though were only taken during the adjuvant chemotherapy and therefore could be a variable duration from what I understand. Right? Great. Dr. Carolyn Lam: So Geeta then, could you tell us what did the extended analysis show? Dr. Geeta Gulati: The extended follow-up was interesting and it was something we really wanted to figure out because there are not many studies who have been done on the extended follow-up and you're not giving these study medications afterwards. Dr. Geeta Gulati: So very interestingly we saw that the decline in the ejection fraction was still there in the whole group. But this time there was no difference in the group who received Candesartan do those who didn't. And we show that there was a different in the primary results, but now in the extended follow-up there was no difference. And then also in the Metoprolol group that had previously shown that there was lesser rise in the troponins. Again, there was no difference in the groups now on the extended follow-up. Dr. Geeta Gulati: So this is very interesting because this shows that there is a small, modest decline in a left ventricular ejection fraction during and after the breast cancer therapy. But what does this really mean? It's a small decline and it's within the normal range and the cardioprotection is not working. So, are we perhaps looking at the wrong group? Perhaps we should look at patients who have the higher cardiovascular risk factors. Perhaps even we should look at more novel heart failure or cardiac drugs that may have a stronger effect on the ejection fraction. Dr. Carolyn Lam: Right. So Geeta though, can we unpack that a little bit? You see, the patients were not on the medication anymore at the time of follow-up. So you're saying that even though they were given adjuvant chemotherapy and covered with the drug, that even not having any more chemotherapy, their ejection fraction still fell. And if I'm not wrong, this was an MRI analysis. And so it was only by an ejection fraction of two percent on mean fall, right? How do we think about that clinically? Dr. Geeta Gulati: And that's the important question, isn't it? Because a decline in the ejection fraction of less than two percent within the normal range, what does it really mean? Well initially we thought that if there was a different in those who had cardioprotective medication compared to those that didn't, it may prevent development of further decline in the cardiac function and then heart failure in the future. But now, there is really no difference between the groups. So perhaps the clinical implication of giving cardio protection to all cancer patients is not really that useful. Perhaps they should look at those who are at higher risk because they would have a greater fall in ejection fraction and then more cardioprotective effect of these drugs. Dr. Carolyn Lam: Yeah, totally. And perhaps the metrics that we're used to seeing in the past with greater falls of ejection fraction, maybe it just doesn't apply currently or perhaps with the specific chemotherapeutic regimens perhaps that you're using now. Because with a very small fall, and I believe you only had one heart failure event, right? If I'm not wrong in this extended follow-up. So, just to let the audience know, it was very small fall, little number of events. It's hard to really tease apart what that clinically means. Now, could I ask though, does it mean we need actually a more sensitive marker? Because there was some interesting stuff about global longitudinal strain. Could you- Dr. Geeta Gulati: I would throw that question back to Torbjørn I think. Dr. Torbjørn Omland: Yes. So that's a very interesting question Carolyn. So we did observe what seemed to be a beneficial, but a sort of minor effect on global longitudinal strain. So we know that that is the more sensitive index of systolic function than left ventricular ejection fraction, that was the pre defined primary outcome. So that's raises of course questions whether a future trial should more focus on these more sensitive indices of cardiac function. Dr. Carolyn Lam: Yeah. Geeta, could I then really put it back to you? And the tough question I always get, how do we apply these results clinically then? I mean, you see these patients right? Now what? Do you give or do you don't give? And which one do you give? And how do you identify high risk patients? I don't know. Dr. Geeta Gulati: Again, I think all the patients are unique aren't they? So that's where we have to start. So in my clinic, if I have a high risk patient with hypertension, diabetes, hypercholesterolemia, yeah perhaps they even have had a cardiovascular disease before something like this. Then I will take more care of these patients and be more careful with the echo measurements I'm doing and if I find that they have a decline in their cardiac function, I may be more eager to start them on cardioprotective medication. Dr. Geeta Gulati: But then in R-Regen we follow all the HER two positive breast cancers with echo. If I don't have echoparamaties that clearly tells me that they have a decline in the cardiac function, then I may wait to start cardio protection because none of the studies has really so far show that all patients should have these cardioprotective medication or prevention. Dr. Carolyn Lam: Nice. Thank you. That was a tough one to get at. And I suppose Torbjørn I have to give you another tough one then. Because how to address the remaining unanswered questions, right? Because one of them on my mind too, is how to identify the high risk, do biomarkers play a role? And then the other is if we then start the preventive therapies like ERBs and beta blockers, should we actually continue it forever? And so on. But anyway Torbjørn please, please, what does the future hold? Dr. Torbjørn Omland: I think it's worthy of a recap or underscoring that these are really good news for many breast cancer patients that actually the risk of an important decline in ventricular function is lower than we thought. So that may be because of several things. I think in general, those whose used these cardiotoxic drugs are lower. And we also, I think that there's increased collaboration between oncologists and cardiologists. Also meaning that we are better to pick up the high-risk patients at an early stage. Dr. Torbjørn Omland: But of course, it's very important questions that you asked regarding how to identify the high risk patients. And I think that's where really future research should focus. So there we know that traditional risk factors are important. We are looking into whether biomarkers can be used, if there's more sensitive imaging in this can be used. But so far we haven't really succeeded in getting the risk model that really identifies it on the patient level. So that's work that remains to be done. Dr. Torbjørn Omland: And then we are also looking for new types of intervention, good exercise, good other drugs. We are doing now a PRADA two study where we look at the effects of Sacubitril Valsartan in this setting. And those are also very exciting, I think, and we look very much forward to present that in the future. Dr. Carolyn Lam: Oh wow thank you so much Torbjørn and Geeta. The PRADA two trial. I've got to ask you, why do you then call it the Chanel trial? But I think I'll save that for another day. So thank you. Thank you once again, this is fabulous and congratulations to you both. Dr. Torbjørn Omland: Thank you. Dr. Geeta Gulati: Thank you. Dr. Greg Hundley: Well listeners, welcome to our second feature discussion today. And we have with us Dr. Marc Dweck from University of Edinburgh in Scotland and our own associate editor, Victoria Delgado from Leiden in the Netherlands. Welcome to both of you. Dr. Greg Hundley: Marc, we're going to get started with you. Could you tell us a little bit about the background for your study and what was the hypothesis that you wanted to test? Dr. Marc Dweck: Thanks very much Greg for the invitation. So I guess aortic stenosis is perhaps the last major cardiovascular condition where we don't have a medical therapy. We're unable to treat these patients. We're unable to prevent progression. We're only left with a valve replacement. And so we, like a lot of groups around the world, want to develop a treatment for aortic stenosis. Our group did the first SALTIRE trial, where we looked at statins seeing if we could slow aortic stenosis progression. And that, like similar trials, was neutral. No effect on the valve progression. Dr. Marc Dweck: And so actually I've spent the last 10 years looking at some of the factors associated with aortic stenosis progression in particular. The answers that we've had from those trials have kind of come back telling us that really it's a process of calcification. If you look at what triggers progressive valve narrowness is this calcific process, that seems to be a self perpetuating disease. Dr. Marc Dweck: So the question is, how do you target this calcification process? How can you interrupt it? And how can you do that without compromising bone health in these elderly patients? So in trying to come up with a solution to that we thought about using osteopetrosis agents, which we hypothesized would maintain both bone health and reduce vascular calcification on the basis of observational data and also animal data suggesting that. And that was really where we came from in the design of the SALTIRE two trial. Dr. Marc Dweck: And doing a big trial with clinical endpoints wasn't felt to be feasible and instead we decided to look at imaging end points and see whether we could slow disease progression using these agents. Dr. Greg Hundley: Very nice Marc. And so you're really leading us into, tell us a little bit more about your study population and your study design. Dr. Marc Dweck: Yeah so we wanted to take patients from our outpatient clinic with mild, moderate and even early severe disease, asymptomatic patients crucially, patients that aren't scheduled for aortic valve replacement and see the effects of these drugs on disease progression. Dr. Marc Dweck: So we did a randomized control trial. There was three arms. Patients were randomized to Alendronate, Denosumab, these are the two osteopetrosis agents, or placebo. We then did a series of baseline imaging tests. So the primary end point was based on CT calcium scoring. So they had a baseline CT calcium score. They also had a baseline echocardiogram and they had a baseline fluoride PET scan. So this measures calcification activity in the valve. And then we essentially repeated those tests after a period of time on the drugs, or on placebo. We repeated the calcium score and the echo after two years and repeated the PET scan after one year. Dr. Greg Hundley: Very nice, and so before you tell us your results, a little bit, how many patients? And maybe their average age and the rough distribution of men versus women. Dr. Marc Dweck: Yeah so study recruited roughly 50 patients in each arm. The average age was 72 and there was 21% females in the study. So, like a lot of studies in aortic stenosis, a low female prevalence. Despite our best efforts, that's something we need to attend to in the future, but otherwise, a representative age group and patients with this disease. Dr. Greg Hundley: And what did you find? Dr. Marc Dweck: Well we found that the drugs didn't have an effect on any of these imaging assessments. So, there was no effect on the progression for CT calcium score at two years, no effects on any of the echocardiographic assessments of hemodynamic severity, and no effect on calcification activity as measured with the fluoride. Dr. Marc Dweck: So a very consistent result using multiple different imaging modalities, which I think gives us confidence that there isn't at least a dramatic effect of these drugs on disease activity or disease progression, in aortic stenosis. Dr. Greg Hundley: Very good. Well listeners, we're now going to turn to one of our associate editors, Dr. Victoria Delgado, and she is really a valvular heart disease expert member of our team. Dr. Greg Hundley: Victoria, I know you see a lot of papers that kind of come across your desk. What attracted you to this manuscript? And then how do you put the results in the context of other research that's going on to halt the progression of aortic stenosis. Dr. Victoria Delgado: Thank you Greg. So first the first thing that attracted my attention for this article is the question. We know that we don't have any medical therapy for halting the progression of aortic stenosis. And even if the previous studies have been negative or neutral, still there is the interest of trying to find a less invasive therapy for these patients, or even prevent that they arrive to surgical or transcatheter aortic valve replacement. Dr. Victoria Delgado: And the second is that these are very strong analysis because it's a randomized clinical trial and using as end points imaging. So that trial also in a way answers the question of which imaging technique we need to use in order to see the effects of specific therapies. Previous studies have used mainly echocardiography, but that only gave us information on the modynamic effects of the aortic stenosis. While in this study, we have the combination of CT and a combination of a PET that he give us also information on how the calcification is happening. So that makes the study very comprehensive and give us more insights into this pathophysiology, to this pathology particularly. Dr. Greg Hundley: Very nice. So it sounds like looking at aortic stenosis from multiple different angles, whether it be echocardiography or perhaps imaging processes that look at the progression of calcification. Dr. Greg Hundley: Well, Marc, I want to come back to you. What do you think is the next, sounds like you've been working in this area for an extended period of time. What do you see as the next research study that you and your group may undertake in this area? Dr. Marc Dweck: I Think we've got the study design about right. I think if in the future studies we want to do, I think we would adopt a similar design using these imaging end points. Dr. Marc Dweck: I have to say I'm very influenced by the recovery trial that has been conducted in the UK with COVID. I mean, here's a disease where we wanted to get a treatment as quickly as we can. And in doing that, developing a platform type trial where you potentially test multiple different promising agents simultaneously across multiple centers across the world or the UK, I think that would be the quickest way to developing a treatment. And so I'm encouraged that there are five or six very good targets where we could, for a new therapy in aortic stenosis. And I think a platform type design where we engage multiple groups using imaging as that initial end point. And then, the drugs that appear to have an effect on these imaging end points we can start to recruit more patients at those sites, into those centers, looking for clinical end points. Dr. Marc Dweck: I think that kind of discussion is happening around the world now between groups that are interested because we want to crack this problem quickly. We don't want to wait and do these different studies sequentially. We want to try and do them simultaneously. And I'm excited about that. I think if we do that, we've got a real shot at developing a treatment over the next five to 10 years say. Dr. Greg Hundley: Fantastic. Dr. Greg Hundley: And Victoria, I know you have interest in this particular area. Do you have anything you'd like to add? Dr. Victoria Delgado: Yeah. I think that those studies that Mark said are really welcome and I hope that they are positive. And give us a little bit of more to treat these patients. My main fear is that these patients are not as frequent, for example, as heart failure patients. Where we have several therapies where we have possibility to enroll patients in trials for new drugs, that we know that probably are going to be effective. But for valvular heart disease it has been always the end point to reach surgery or to reach an aortic valve replacement or indication of the mitral valve and mitral valve repair. So in early phase of the disease, my main concern is that maybe the patient is not going to be well-trained to understand what are the consequences. I want to always wait until maybe when is needed for the surgical or transcatheter procedure. Dr. Victoria Delgado: But I think that increasing the awareness of the prevalence of valvular heart disease and the consequences may help people to understand, to put more attention for an early diagnosis and develop new drugs that can help, like in this case, aortic stenosis one of the most frequent valvular heart disease, to prevent the proliferation and to prevent the replacement of the valve. Dr. Greg Hundley: Very nice. Well listeners, this has been a wonderful discussion and we greatly appreciate the input that we've been able to gather today from Dr. Marc Dweck from Edinburgh in Scotland and our own associate editor, Dr. Victoria Delgado. Bringing this information from a randomized trial, evaluating osteoporosis drugs, and really indicating they did not disrupt the progression of calcification in patients with aortic stenosis. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to wish you a great rest of your week and we will catch you next week on The Run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

So… this episode is kind of a big deal. We’ve hit the 150th episode of the show with over 220,000 downloads and counting. I’ve been considering how I wanted to celebrate it for months. Should I have some super high-profile guest? Should I do it solo? Or should I do something different? After a few weeks, the answer became clear. I want to use this moment to let you in what’s been going on over here. I’ve been secretly co-creating a second business with two amazing women. Women who are not only doing really important work in the world, but who I know are soul-mate level friends. That’s Alissa Alter and Anne Omland. Alissa is a Women’s Health Expert & Motherhood Advocate, author of Unstuck: From Understudy To The Study Of Your Undercarriage, and host of the podcast Myth of Motherhood who is all about cracking open the taboo topics of pregnancy and motherhood. She uses movement, mindfulness, and good ol’ education to help mamas and mamas-to-be stop suffering in silence so that pregnancy, childbirth, and postpartum can be healing and empowering stages of life. Anne is a Yoga & Meditation Teacher, Hypnobirthing Childbirth Educator, Women’s Health Coach, Doula-in-training and the founder of Mamakind, a platform where she creates personalized wellness plans that care for the whole woman on her journey to motherhood. In her former career, she was a VP at a Fortune 500 company and struggled with workaholism, and later found it challenging to become pregnant. She realized a deep disconnect between not only how our systems of care support women in their motherhood journey but also between her and her body. Six years and 3 little ones later, she’s found a passion in supporting women as they look to conceive, navigate pregnancy, and as they transition into new motherhood. As you’ll hear in the episode, these two went through my Your Wellness Brand Program in 2020 to build their businesses. I felt an instant connection with both of them—like we’d known each other for years. And over the summer, when I got the download for this new venture, I knew I couldn’t do it alone. In this episode, we chat about why both Anne and Alissa were a hell yes to co-founding a company together, the challenges that we each experienced after having babies and how there is a huge missing link for all women and birthing people, why the postpartum experience is so screwed up, what we believe it should be like, and how our platform will be part of the solution, and so much more!   To learn more about Alissa Alter, Anne Omland, and the resources mentioned in this episode, visit the show notes.   Follow Me On: Facebook Instagram

Jan vom (ehemals) größten deutschen Aufklärungskanal auf Youtube spricht mit mir über seine kürzliche Kanallöschung, Youtube im Allgemeinen aber natürlich hauptsächlich über sein Kernthema. War ne schöne Folge, viel Spaß Leute. Jans Homepage: https://www.61minuten.de/ Jans Quellen: Als QUELLEN werden Metaanalysen (MA) bevorzugt, doch wenn es um spezifische Fragen geht, liste ich manchmal auch einzelne Studien (S). 1) MA: Pornos hängen zusammen mit 2. Verzögerter Ejakulation 3. Erektiler Dysfunktion 4. Veränderungen sexuellen Verlangens und 5. sexueller Befriedigung https://bit.ly/35m4nic 2) MA: Erektile Dysfunktion steigt Weltweit signifikant, seit es Internet-Pornos gibt. Quellen 70,71,72 zeigen Dopamin Auswirkungen und Abschnitt 3.1 enthält zahlreiche Quellen über neuro-plastische Veränderungen https://bit.ly/35ngEmH 3) S: Durch Exposition neuer Partnerinnen sank die Ausdauer um 1,78min (p = 0.045) und die Spermaqualität stieg signifikant an https://bit.ly/3hgMT9l 4) S: Porno Sucht korreliert mit Alltagsstress und der Motivation Pornos für sexuelle Befriedigung und als emotionale Vermeidungsstrategie zu konsumieren. https://bit.ly/3maQ4Ts 5) MA: Männer können genitale Erregung besser (r=.66) einschätzen, als Frauen (r=.26) https://bit.ly/2ZmiRe6 6) Vor vielen Jahren war dieses Buch und die darin enthaltenen Quellen mein Startpunkt der Recherche. Obwohl seit 2003 viele Studien hinzu gekommen sind, empfehle ich Dir dieses Fachbuch für Ärzte als Ausgangspunkt Deiner Recherche: Ejaculatio praecox: Therapiemanual von Thieme https://amzn.to/3bHd0VT * Die von mir entwickelte „AUSDAUER CHALLENGE“ hilft betroffenen Männern. Sie richtet sich nicht an Fachleute. https://www.61minuten.de/AUSDAUER-CHALLENGE Die Meinungen der Gäste können, müssen aber nicht mit meinen Meinungen übereinstimmen. Videoversion auf https://www.youtube.com/channel/UCi_Y8rdLSLufgcPseYe0JSg zukünftige Podcastfolgen live mit Bild auf https://www.twitch.tv/impimpimp

This week's episode features author Torbjørn Omland and Senior Guest Editor Vera Bittner as they discuss the artile "Growth Differentiation Factor-15 Provides Prognostic Information Superior to Established Cardiovascular and Inflammatory Biomarkers in Unselected Patients Hospitalized with COVID-19." TRANSCRIPT BELOW: Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary, and backstage pass to the journal and its editors. We are your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: I'm Dr. Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn our feature this week gets into inflammatory biomarkers in patients that have been hospitalized with COVID-19, but before we get to that, how about we grab a cup of coffee and work through some of the papers in the issue. Would you like to go first? Dr. Carolyn Lam: Absolutely. With both the coffee and the papers. So great, for this first paper, have you thought about concentric versus eccentric cardiac hypertrophy? We traditionally associate them with pressure versus volume overload respectively in cardiovascular disease, both though conferring an increased risk of heart failure. These contrasting forms of hypertrophy are characterized by asymmetric growth of the cardiac myocytes in mainly width or length respectively. However, the molecular mechanisms determining myocyte preferential growth in width versus length remain poorly understood. Dr. Carolyn Lam: That is until today's paper, and it is from Dr. Kapiloff from Stanford University, and Dr. Rosenfeld from UCSD, School of Medicine and their colleagues, and what they did was used primary adult rat ventricular myocytes, as well as Adeno associated virus mediated gene delivery in mice, to define a regulatory pathway controlling pathological myocyte hypertrophy, and they found that asymmetric cardiac myocyte hypertrophy is modulated by serum response factor phosphorylation, constituting an epigenomic switch balancing the growth in width versus length of adult ventricular myocytes In vitro, and In vivo. Dr. Carolyn Lam: Serum response factor phosphorylation was bi-directionally regulated at signalosomes organized by the scaffold protein muscle, A kinase anchoring protein beta. This newly identified molecular switch controlled a transcriptional program responsible for modulating changes in cardiomyocyte morphology that occurs secondary to pathological stressors. Dr. Greg Hundley: Very nice, Carolyn. So switches controlling this transcriptional program. Tell us a little bit, and bring us back to the clinical relevance of this and starting with that concentric versus eccentric hypertrophy? Dr. Carolyn Lam: I thought you may ask. The identification of a molecular mechanism regulating that asymmetric cardiomyocyte growth, really provides a new target for the inhibition of pathological cardiac hypertrophy. Studies in mice using these Adeno associated virus based gene therapies to modulate that signalosome, really provided proof of concept for translational potential in the treatment of pathological cardiac remodeling and prevention of heart failure. Dr. Greg Hundley: Oh, wow. Very nice, Carolyn. Well, my first paper comes to us from Professor Dirk Westermann from Hamburg, and focuses on cardiogenic shock patients, and veno-arterial ECMO, the results from the international multicenter cohort study. So Carolyn this study evaluated data from 686 consecutive patients with cardiogenic shock treated with VA ECMO with or without left ventricular unloading using an Impella, and they conducted this at 16 tertiary care centers across four countries. They examined the association between left ventricular unloading and 30 day mortality. Dr. Carolyn Lam: Huh, so what did they find? Dr. Greg Hundley: Okay. Carolyn. Well, left ventricular unloading was used in 337 of the 686 patients enrolled, and after propensity matching 255 patients with left ventricular unloading were compared with the 255 patients without left ventricular unloading. In the match cohort, left ventricular unloading was associated with lower 30 day mortality without differences in the various subgroups. However, complications occurred more frequently in patients with left ventricular unloading, like severe bleeding, which happened in 38.4% versus only 17.9% in those without unloading. There was also access-related ischemia and renal replacement therapy. Dr. Greg Hundley: So Carolyn, the take-home message from this International multi-center cohort study, is that left ventricular unloading is associated with lower mortality, and cardiogenic shock patients treated with VA ECMO, despite higher complication rates. In the absence of randomized trial data these findings support the use of left ventricular unloading and cardiogenic shock patients treated with VA ECMO, and call for further validation, ideally in a randomized controlled trial. Dr. Carolyn Lam: Very nice. Well for my next paper, Greg, it's all about desmin. Now we know that mutations in the human desmin gene caused myopathies and cardiomyopathies. Well, today's authors, Dr. Hermann and Schroeder from University Hospital Erlangen in Germany and Dr. Lilienbaum from University of Paris and France and their colleagues, report an adolescent patient who underwent cardiac transplantation, due to restrictive cardiomyopathy caused by a heterozygous R406W desmin mutation. Sections of the explanted heart were analyzed with antibodies specific to 406W-desmin, and to intercalated disc proteins. Effects of this mutation on the molecular properties of desmin were then addressed by cell transfection and In vitro assembly experiments. They further generated these desmin mutation knock-in mice haboring the orthologous form of the human, R406W-desmin. Dr. Greg Hundley: So Carolyn, what did they find? Dr. Carolyn Lam: Well, they demonstrated a novel pathomechanism in which cardiotoxic R406W-desmin, could adapt dual functional status with the abilities to integrate into the indogenous intermediate filament network, and to cause formation a protein aggregates. This R406W-desmin modified the extra sarcomeric cytoskeleton, such that desmin filaments were not anchored to desmosomes anymore. Thereby destroying the structural, and functional integrity of intercalated discs. Dr. Greg Hundley: What are the clinical implications? Dr. Carolyn Lam: Well, since these cardiotoxic desmin mutations could affect the integrity of intercalated discs, thereby inducing conduction defects and malignant arrhythmias, they suggest early implantation of pacemaker, or cardioverter defibrillator devices, may be considered to prevent certain cardiac death in patients with these mutations. Furthermore, state-of-the-art basic molecular risk stratification of desmin mutations may encompass a multidisciplinary experimental approach as exemplified by the approach taken here, which comprises assessment of the tissue pathology in conjunction with genome analysis and desmin assembly studies as well as patient mimicking cell and animal models for the In vivo validation of these mutations. Dr. Greg Hundley: Well, fantastic, Carolyn. Well, my next paper comes to us from Dr. Ravi Shah from the Massachusetts General Hospital. This study evaluated 2,330 white and black young adults, average age of 32 years, in the Coronary Artery Risk Development in Young Adults, or the cardiac study, to identify metabolite profiles associated with an adverse cardiovascular disease phenom that included, myocardial structure and function, fitness, vascular calcification, and then also mechanisms, and other cardiovascular outcomes that would occur over the next two decades. Statistical learning methods, including elastic nets and principal component analysis, and Cox regression generated parsimonious metabolite based risk scores, validated in over 1800 individuals in the Framingham Heart Study. Dr. Carolyn Lam: Wow. What did they show, Greg? Wow, that's a lot of work. Dr. Greg Hundley: Yeah. So Carolyn, the authors found two multiparametric metabolite-based scores linked independently to vascular, and myocardial health. With metabolites included in each score specifying microbial metabolism, hepatic steatosis, oxidative stress, nitric oxide modulation, and finally collagen metabolism. Over nearly 25 year median follow-up, and cardia, this metabolite based vascular score, and the myocardial score, and the third and fourth decade of life were associated with clinical cardiovascular disease. Importantly, the authors replicated these findings in 1,898 individuals in the Framingham Heart Study followed over two decades, such that young adults with poor metabolite based health scores had higher hazard ratios of future cardiovascular disease related events. Dr. Carolyn Lam: Oh wow. Greg, what an elegant study with both development and validation cohort evaluating the metabolome. Dr. Greg Hundley: Yes. Carolyn. So metabolic signatures of myocardial, and vascular health in young adulthood specify known novel pathways of metabolic dysfunction, relevant to cardiovascular disease associated with outcomes in two independent cohorts. So these data suggests that efforts to include precision measures of metabolic health in risk stratification to interrupt cardiovascular disease at an early at stage, are warranted. Dr. Carolyn Lam: Wow. So interesting. Other very interesting articles in today's issue, there's an In Depth article by Dr. Angiolillo entitled, “The Antithrombotic Therapy for Atherosclerotic Cardiovascular Disease Risk Mitigation in Patients with Coronary Artery Disease and Diabetes.” There's also Research Letters, one by Dr. Sultan on, “The Longterm Outcomes of Primary Cardiac Lymphoma” and one by Dr. Wang on, “Loss of Phosphatase and Tensin Homolog Promotes Cardiomyocyte Proliferation and Cardiac Repair Following Myocardial Infarction.” Dr. Greg Hundley: Great, Carolyn. Well, I've got a couple other articles in this issue as well. One is by Professor Ganesan Karthikeyan who has an On My Mind piece entitled an “Alternative Hypothesis to explain Disease Progression in Rheumatic Heart Disease.” Dr. Stuart Chen has an ECG challenge entitled, “Alternating QRS Duration and a Normal T-waves. What is the mechanism?” Then finally, Carolyn, a series of Letters to the Editor, one by Dr. Peterzan and the other by Dr. Mehmood regarding the prior published article, entitled “Cardiac Energetics in Patients with Aortic Stenosis and Preserved Ejection Fraction.” Well, Carolyn, how about we get onto that feature article and learn more about inflammatory biomarkers in hospitalized patients with COVID-19? Dr. Carolyn Lam: Yes. Let's go. Greg. Biomarkers are really playing an increasingly important role in cardiovascular disease, and even in the current COVID 19 pandemic, there's been a lot of news about how biomarkers such as traponin may be prognostic, and in fact, we're all wondering about maybe even newer biomarkers. In fact, today's feature discussion does bring to light one of the newest, and in fact, this is the first publication on the role of Growth Differentiation Factor 15 or GDF-15 in COVID-19. We're so pleased to be discussing this with the corresponding author, Dr. Torbjørn Omland from University of Oslo, in Norway, as well as our senior guest editor, Dr. Vera Bittner from University of Alabama at Birmingham. So welcome both. Tobjorn, could you tell us a little bit about GDF-15 and what made you look at it, and what did you find? Dr. Torbjørn Omland: Yeah, so GDF-15, that's a very interesting biomarker. It's considered a biomarker of biological aging cellular stress, and perhaps also the inflammation, and tests being studied within the cardiovascular field for some years now, and it has been shown to be a strong prognostic indicator across the cardiovascular spectrum, actually. So it is a new biomarker in one sense, but there are some data already in the cardiovascular field. Dr. Carolyn Lam: Not in COVID. So this is the first study to really look at its prognostic value in COVID 19. So congratulations Torbjorn, and if I may also to the first author, Dr. Peter Meer, a good friend as well, but please, could you tell us about your study and what you found? Dr. Torbjørn Omland: Yes. So when the COVID pandemic hit Norway in the spring, we thought that we should plan a prospective biomarker study. So we had to really fast track approval by the IRB and so forth, and we're able to actually cover most of the patients that were hospitalized in our hospital, Akershus University hospital, which is right outside of Oslo, and it's a pretty large hospital by Norwegian standards. It covers about 11% of the Norwegian population. Dr. Torbjørn Omland: So in that period, when we were including, we had 136 patients hospitalized with confirmed COVID 19, and we have biobank bank samples from 123 of these, and then there have been reports from retrospective studies, first from China, that seemed to suggest that markers like cardiac troponin, Anti-Troponin T, and Ferritin were associated with outcome, but those studies were prone to selection bias in that the measurements were performed in the most sick patients. So in this study we included all patients and then we thought we should examine a broad panel of biomarkers, and that included Interleukin 6, CRP, Procalcitonin, Ferritin, and the D-dimer Cardiac troponin, and N-terminal pro B, and GDF-15. Dr. Carolyn Lam: Wow. Thank you, Torbjorn. Even before you carry on with the results, can I just say having visited your hospital in pre-COVID days, I can only imagine what a work of love this was to do it prospectively. Any particular experiences to talk about, to get a fast-track even in the midst of to perform a well done prospective study, that must have taken a lot. Dr. Torbjørn Omland: Yes. But it's also interesting in that the whole sort of ablation on Norway was very much into this from the highest political level. Also, the decision that the older research on COVID should be prepared to retire, then the IRB had an eight hour and deadline for them to approve or not approve the study. So that's went surprisingly smoothly, I must say. Dr. Carolyn Lam: Wow, that's great. So what did you find? Dr. Torbjørn Omland: Yeah, so we found that among these biomarkers, several seem to predict outcome, and the primary end point of this study was to combined end-point of the hospitalization in the ICU, or death. We found that also markers like cardio traponin, BNP, ferritin, and the D-dimer and so forth, in univariable analysis, were very associated with outcome, but when we perform a more comprehensive, mostly variable modeling, then the prognostic value of some of these markers disappeared. In contrast, for GDF-15, it seemed to perform very strongly, both on the baseline sample, and interestingly also it increased in those reaching the primary end-point during the hospitalization. So it provided a very strong and independent information also when we adjusted for clinical risk scores, like the NEWS score. So that was a very pleasant surprise to see that there was one marker that's actually performed so well. The other marker that's also performed well was Ferritin. Dr. Carolyn Lam: Very interesting, and so the new score being the National Early Warning Score. Thank you. Verra, I really love to bring in your thoughts. I mean, could you take us behind the scenes with the editors? What did you think when you saw this paper? Dr. Vera Bittner: As you know, I mean, a lot of journals have been inundated by COVID papers, and so this one stuck out to us, because it's the first time that we had seen that anybody linked GDF-15 to a COVID population, even though it has been out in the literature for ACS, and in my prognostication, and in a healthy populations, and in chronic coronary disease populations, heart failure, and so on. So this is the first time that we've seen it applied there. Dr. Vera Bittner: Then I would echo some of the things that Torbjorn said, that we were also impressed, that it was prospective, because when you look at some of the other biomarker studies, what was prognostic in one with then not shake out the other one, because either different variables were included in the models, because the population's differed. So to have something that was representative of the population that was actually admitted to this, Norwegian Academic Hospital, stood out to us. So we're excited to get this paper basically for circulation, and hope that it also will be impetus for future research. Dr. Carolyn Lam: Thank you so much for sharing that end for helping us publish such a beautiful paper. Did you have some questions for two of your own? Dr. Vera Bittner: Yeah. So what stuck out to me is that you had this a whole crew of biomarkers, and then when you looked ultimately at the final model, there were two that were standing out, that was ferritin, and it was the GDF-15, and then when I looked at your graph, it looks like not only did these biomarkers measure different contrasts, but their time-course also seemed to be different, and so I was just wondering whether you had thought about, maybe using these to joint the model outcome, and whether we might even be able to get more information that way. Dr. Torbjørn Omland: I think that's an excellent suggestion, and as you correctly pointed out, they do have different sort of profiles and ferritin being an acute phase reactant, having various sort of dramatic early rise whereas we see that GDF-15 increased progressively during the course of hospitalization in the most severe patients. I think when combining them, is actually a great IMT that we should look further into. Dr. Carolyn Lam: Very nice. Torbjorn, if I could, I've got a couple of questions too. So 123 patients, 35 of whom had the primary outcome, right? So that may be sort of seen as, is this too small? and they're all hospitalized patients. So could I ask, what do you predict maybe seen in a larger population or outside of Norway or in a non-hospitalized population? Dr. Torbjørn Omland: So as you say, we were early with this report, but since it was submitted, there has been a couple of smaller studies that seemed to confirm our results. So that is reassuring, but of course we would like to have studied this in logical patients. We are in touch with the other biobank samples that could possibly confirm the data. So that's one obvious step. Then it's very interesting, as you say, could we sort of expand this to also apply to non-hospitalized patients? I think that it would be a very interesting hypothesis to test, and I think there's still a pretty good rationale for this. Dr. Torbjørn Omland: It's interesting that the insoluble group actually showed a correlation that when the soluble ST2 concentrations and GDF-15. So there might be that those with more susceptibility to COVID infections, actually, I thought that, that is actually reflected by GDF-15 concentrations, but the challenge is how to sort of get a representative non-hospitalized population, but interestingly, I was approached by some of the hospital staff that actually are in contact with general practitioners, and wanted sort of implement this test also for this group. Dr. Carolyn Lam: So Verra, we're really grateful that Allan Jaffe was working with you in managing this beautiful paper, and if you don't mind me cheekily paraphrasing that you said you might channel him, if you could, what would the channeled Allan Jaffe perhaps say about what's needed in this whole biomarkers fear in COVID-19? Dr. Vera Bittner: Hopefully, many. A channeling element is obviously difficult, because he is such an incredible expert on biomarkers that I can't even pretend to be able to see, that you might be thinking, but it seems to me that one thing that we could all agree on is that it would be really exciting if something like the: get with the guidelines COVID registry, could decide to measure this marker perspectively in the participating hospitals, for example. Dr. Vera Bittner: Then be able to look at this in a much, much larger population. I mean, especially with different ethnic backgrounds as well. I mean, I noticed actually to my surprise that, this Norwegian study how to fairly high proportion of Asians in the sample, but that may not be the ethnic distribution that we might see in different regions of the US, or different regions of the world. So it would be really nice to incorporate the measurement of this biomarker in much larger datasets. So things can be explored a bit further. Dr. Carolyn Lam: That's excellent, and Torbjorn, if you could channel Allan. What would you say? Dr. Torbjørn Omland: That's a difficult path, but absolutely just to me what Verra said. Then I think the importance of prospective studies in the COVID biomarker field, I think is our at most importance. Dr. Carolyn Lam: I think on behalf of both Torbjorn and I, and in fact everyone in circulation. Thank you, Verra for the amazing work that you and your team do for circulation as well. Thank you so much for making the time to share your thoughts today and thank you for that beautiful, beautiful paper both of you. Thank you. (singing). Listeners you've been listening to Circulation on the Run. Thank you for joining us from Greg and I. Don't forget to tune in again next week. Dr. Greg Hundley: This program is copyright, the American Heart Association 2020.  

This week’s episode features author Kazuomi Kario and Associate Editor Wanpen Vongpatanasin as they discuss the article "Nighttime Blood Pressure Phenotype and Cardiovascular Prognosis: Practitioner-Based Nationwide JAMP (Japan Ambulatory Blood Pressure Monitoring Prospective) Study." TRANSCRIPT BELOW: Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, when is the best time to check your blood pressure if you have a home monitoring device? Morning? Afternoon? Nighttime? And what do those nighttime fluctuations infer? Well, we'll hear a lot more in our feature discussion today, but first let's grab a cup of coffee and jump into some of the other papers in the issue. I'm going to start first this week, and my first paper comes from Dr Joe Wu at Stanford University. Carolyn, a quiz. Are all endothelial cells alike? Dr Carolyn Lam: Jeez, Greg. Okay, I'm going to hedge. I bet a lot of them share similarities, but there may be some differences. Dr Greg Hundley: Yes, Carolyn. Dr Wu and his associates perform a series of elegant experiments involving mice, and they found that certain tissue-specific endothelial cells cluster strongly by tissue, like those in the liver or the brain, whereas others from, for example, adipose tissue or the heart have considerable transcriptomic overlap with endothelial cells from other tissues. They identified novel markers of tissue-specific endothelial cells and signaling pathways that may be involved in maintaining their identity, and sex was a considerable source of heterogeneity in the endothelial transcriptome. In addition, they found that markers of heart and lung endothelial cells in mice were conserved in human fetal heart and lung endothelial cells and identified potential angiocrine interactions between tissue-specific endothelial cells and other cell types by analyzing ligand and receptor expression patterns. Dr Carolyn Lam: So interesting, Greg. You especially had me at sex differences. So, what's the take home message? Dr Greg Hundley: Right, Carolyn. So this group discovered a series of transcriptional networks that maintain endothelial cell heterogeneity, and that angiocrine and functional relationships exist between tissue-specific endothelial cells. These findings open the door for future studies that can manipulate these pathways and perhaps modify processes, like atherosclerosis, that impact the endothelium. Dr Carolyn Lam: Wow, that's cool, Greg. Well, from your paper, I'm going to a mechanistic paper too, and the next study really aimed to define cardiac fibroblasts' heterogeneity during ventricular remodeling, as well as the underlying mechanisms that regulate their function, so important questions here. And co-corresponding authors, Drs Prósper and Lara-Astiaso from Clinica Universidad de Navarra in Pamplona in Spain, as well as Dr Lindner from Maine Medical Center Research Institute in Scarborough, Maine in the U.S., and their co-authors, basically characterized cardiac fibroblasts after myocardial infarction using a whole host of very novel techniques like single-cell and bulk RNA sequencing, ATAC sequencing, and functional assays. Swine and patient samples were studied using bulk RNA sequencing. Dr Greg Hundley: Very intriguing. What did they find? Dr Carolyn Lam: They identified and characterized a unique cardiac fibroblast subpopulation that emerged after myocardial infarction in mice. These activated fibroblasts exhibited a clear profibrotic signature expressing high levels of collagen triple helix repeat containing 1 and localized into the scar. Moreover, the absence of this regulator resulted in pronounced lethality due to ventricular rupture. Finally, a population of cardiac fibroblasts with a similar transcriptome was identified in a swine model of myocardial infarction, as well as in heart tissues from patients with myocardial infarction and dilated cardiomyopathy. Dr Greg Hundley: Ah, so important information on how fibroblasts start the scar formation after infarction. So, Carolyn what's the take home message here for this research? Dr Carolyn Lam: Well, this paper really provides important information on cardiac fibroblast heterogeneity, their dynamics during the course of myocardial infarction, and the authors also redefine the cardiac fibroblasts that respond to cardiac injury and participate in myocardial remodeling. This study identifies collagen triple helix repeat containing 1 as a novel regulator of the healing scar process, and as a target for future translational studies. Dr Greg Hundley: Great, Carolyn. You're doing such a great job. This is an issue for double quiz. Have you ever heard of treatments for hypertension incorporating Chinese herbal formula gastrodia-uncaria granules? Dr Carolyn Lam: What? Are you trying to speak Chinese, Greg? Dr Greg Hundley: Yeah (affirmative) Okay. Dr Carolyn Lam: I'm sure you're going to tell us about it. Dr Greg Hundley: Right. So this study is from Professor Yan Li from Ruijin Hospital in Shanghai, Jiao Tong University School of Medicine. Gastrodia-uncaria granules Carolyn, is a mixture of Chinese herbs that dates back many years, I think thousands, and in this study was used in patients with masked hypertension. So in the study, patients with an office blood pressure of less than 140/90 millimeters of mercury, but a daytime ambulatory blood pressure of 135 to 150 millimeters of mercury systolic or 85 to 95 millimeters of mercury diastolic, were randomized one-to-one to receive the treatment of, and I'm going to abbreviate it, GUG versus placebo, 5 to 10 grams twice daily for four weeks. The primary efficacy variable was the change in daytime ambulatory blood pressure. Dr Carolyn Lam: Ah. (affirmative), so did it work? Dr Greg Hundley: Well, in their intention-to-treat analysis, daytime systolic-diastolic blood pressure was reduced by 5 and 3 millimeters of mercury in the GUG group, and 3 and 1.6 millimeters of mercury in the placebo group, respectively. The between group difference in blood pressure reductions was significant, 2.5 and 1.7 millimeters of mercury, and 24-hour blood pressure by 2 and 1.5 millimeters of mercury, but not for the clinic and nighttime blood pressures. The per protocol analysis in 229 patients produced similar results. Only one adverse event, sleepiness during the day was reported and no serious adverse events occurred. So Carolyn, a potentially inexpensive regimen found useful in China for patients with masked hypertension. To learn more of the results of this interesting study, listeners are suggested to review the article in this particular issue. Dr Carolyn Lam: Wow, interesting Greg. Okay. So from hypertension to CABG. Now we know that approximately 15% of saphenous vein grafts occlude during the first year after coronary artery bypass graft surgery, or CABG, despite aspirin use. So can ticagrelor added to standard aspirin improve saphenous venous graft patency at one year after CABG? Now this is the question that Dr ten Berg from St. Antonius Hospital from Nieuwegein in Netherlands, and colleagues sought to answer in the popular CABG trial, which was an investigator-initiated randomized double-blind placebo-controlled multicenter trial of 499 patients with one or more saphenous vein grafts, who were randomly assigned after CABG to ticagrelor or placebo added to standard aspirin. The primary outcome was saphenous vein graft occlusion at one year assessed with coronary CT angiography occurred in 10.5% of the ticagrelor group, versus 9.1% in the placebo group, so that's an odds ratio of 1.29, and it was not significant. The secondary outcome of one year saphenous vein graft failure, which was a composite of vein graft occlusion, revascularization, myocardial infarction in the myocardial territory supplied by the vein graft, or sudden death, well, that occurred in 14.2% of patients in the ticagrelor group, versus 11.6% in patients in the placebo group. Again, not a significant difference. Dr Greg Hundley: So Carolyn, a negative study? What's our take home here? Dr Carolyn Lam: In this randomized double-blind placebo-controlled trial, the addition of ticagrelor to standard aspirin after CABG did not reduce the rate of saphenous vein graft occlusions at one year. Now, this conclusion differs from some other studies that investigated this research question, and this is discussed in this editorial that you got to pick up. It's by Dr Goldman from the University of Arizona. Dr Greg Hundley: Wow, Carolyn. Great job. Well, we've got a couple more articles in this issue, and I'll start by describing a research letter by Dr Daviet regarding heparin-induced thrombocytopenia in COVID-19, and then Carolyn there's a second research letter from our own Torbjørn Omland regarding established cardiovascular biomarkers provide limited prognostic information in unselected patients hospitalized with COVID-19. And then finally, from Dr Chonyang Albert, a case series entitled, The Enemy Within: Sudden Onset of Reversible Cardiogenic Shock with Biopsy-Proven Cardiomyocyte Infection by SARS-CoV2. Dr Carolyn Lam: We've also got an ECG challenge by Dr Sreenivasan entitled, A Red Flag ECG, also known as, and have you heard of this, South African flag pattern. Okay, here's a hint. It's an important, but subtle ischemic ECG change. You got to look it up. There's an On My Mind paper by Dr Alexander on at risk of depriving patients’ life-saving cardiac surgery, and those are the implications of the ischemia trial for CABG. A Research Letter shared by Dr Susen entitled, Endotheliopathy is Induced by Plasma from Critically-ill Patients and Associated with Organ Failure in Severe COVID-19. And finally, in Cardiology News, Tracy Hampton reviews the most recent literature in top journals like Nature, Metabolism, Cell, Stem Cell, and Circulation Research. Wow. Bonanza issue. So cool, but I really want to hear about the different blood pressure patterns now. Let's go to our feature discussion, shall we? Dr Greg Hundley: Absolutely. Here we go. Well, listeners we are excited to get to this feature discussion to learn more about the use of ambulatory blood pressure measures, particularly those that are collected 24 hours and during the nighttime. We have with us, Dr Kazuomi Kario from the Jichi Medical University in Japan, and our own Associate Editor, Dr Wanpen Vongpatanasin from University of Texas Southwestern Medical Center in Dallas. Welcome to you both. And Kazuomi, could you start us off please and just describe some of the background that led you to perform this study? And what hypothesis did you want to address? Dr Kazuomi Kario: The old guidelines management of the hypertension and now recommend instead of the office blood pressure, now the ambulatory blood pressure management. So for example, the ABPN and also home blood pressure monitoring, but the 24-hour blood pressure reduction is very much important, all prefer the values, but also our hypothesis took on the 24-hour blood pressure quantity reduction, but also, we should normalize our circadian rhythm. Usually blood pressure reduced by 10 to 20% at night during the sleep compared to the daytime. But the other group, is exhibited and predicated known six bars and also is either higher at night during the nighttime period compared to the daytime. And also home blood pressure variability, that hurts blood pressure in the morning. So circadian rhythm normalization and also, I recreate blood pressure variability especially is more precise. It's important for the quality control over for the hypertension management. So my hypothesis is that blood pressure reduction, the other most blood pressure, and the normalized circadian rhythm, under agitate, to keep agitate among as such. All the three components I did try to optimize 24-hour blood pressure control, so I want to confirm our hypothesis. To optimize 24-hour blood pressure control consists of these three components, 24-hour pressure reduction, and the normalize circadian rhythm and the keeping the other keep such, it shouldn't be; I have, have you left your prevention or not? That's my hypothesis and background. Dr Greg Hundley: So with our 24-hour ambulatory monitoring evaluating in this study, do we have the normal dip during the evening? Do we have a rise associated with the circadian rhythm? What is the variability of the blood pressure over time? Tell us what study population, and how did you design this study to address your hypothesis? Dr Kazuomi Kario: This population is the hypertension patients, 90% or more on the out-patients who keep the adequate, the active daily readings, and they are medicated, or usually conventional hypertension medication is the effective to reducing the office blood pressure and they can. But the other hypotension treatment may not be sustained to be reducing the nocturnal blood pressure and next morning people are taking pills. So it may be that the picture of the nighttime blood pressure and the morning blood pressure. So our hypothesis targets is already mitigated hypotension patient, but we should find out control for the current hypotension treatment. It should be the nighttime and next morning.   Dr Greg Hundley: So we're addressing whether the efficacy of or any hypertensive medications are maintaining low blood pressures at night and avoiding a surreptitious rise in blood pressure when we wake up. So how many patients did you enroll and what were your study results? Dr Kazuomi Kario: The total study population number is 6,359 patients or enrolls. And we find out, compared to the daytime. Daytime also where the risk of the nighttime blood pressure other age, was more the precise this predictor of cardiovascular events. So, cardiovascular events consist of the atherosclerosis cardiac events consists of stroke and coronary artery disease. And also the nighttime blood pressure associated with the risk of the heart failure. And very interestingly, disrupted circadian rhythm, it rises at night higher during the nighttime compared to the daytime, it was independent of risks for the cardiovascular event, especially for the heart failure. So even after controlling for the daytime, even on the nighttime blood pressure, this pattern nighttime riser was an independent risk, so very interesting results. Dr Greg Hundley: So elevations of systolic blood pressure during nighttime, during sleep were associated with future atherosclerotic cardiovascular disease, as well as heart failure. And one more quick point, was there a particular magnitude of rise of that systolic blood pressure at night was important. And did you find similar results for men and for women? Dr Kazuomi Kario: Yes, similar results for men and the women. Theo other factor was age was increased. The almost the higher during the nighttime or other age of the rising pattern was 10 allowed during the nighttime compared to the daytime. Dr Greg Hundley: So even a 10% increase in systolic blood pressure at night relative to daytime was important for forecasting these adverse cardiovascular events. So Juan pen, can you help us take these results from this elegant ambulatory monitoring study and put those in the context of other study results that have evaluated 24 ambulatory monitoring of blood pressure? Dr Wanpen Vongpatanasin: I think the notion of nighttime blood pressure as the independent predictor of cardiovascular outcome has been shown in other cohort, but usually not this large magnitude, that is an international registry. I had call that in different countries around the world that demonstrate this. But again, like I said, it compiled from a smaller dataset, there's even fewer data sets in the United States. There's a cohort from Jackson Heart, but again, it's less than a thousand and most of other cohorts have looked at mostly a target organ level, not at the heart CV outcome. So I think this add to an important observation, and I think that the results from the nighttime it's similar, but extended from previously that look at individual outcome using a adjudicated data committee that also a very distinctive feature of the study that is a committee that look at this and look at a specific outcome rather than just a retrospective using the death index from different countries. The other part is slightly different perhaps, and they learn from reading it is the extreme dipping, also dropped a lot. Initially people think that it might be associated with the worst outcome, but even to me I wasn't sure what this mean, but in this study the most extreme dip, maybe not, not as much that shouldn't be worried as much compared to the actual nighttime blood pressure itself or not dipping itself. Dr Greg Hundley: Kazuomi what do you see as the next study that needs to be performed in this area of research? Dr Kazuomi Kario: Oh, it's the observational study of the current medical situations maybe kind of situations. So next step, we should focus on that nighttime blood pressure; regardless of the office and the daytime, so even there are controls, if we should target the nighttime blood pressure and the toxicity controls, organ damage should be decreased and the subsequent cardiovascular events should be decreased. So observational study targeting the nighttime blood pressure is the next topic. Dr Greg Hundley: And Wanpen do you have anything to add to that? Dr Wanpen Vongpatanasin:I'd like to see more large observational study from the US with the diverse population, because the salt consumption in Asia, particularly in Japan, are probably among the highest. So perhaps the nighttime blood pressure, it's confounded by high sodium and something, and we're not too far behind obviously, but it'd be nice to know what it means in the US. And obviously they're targeting nighttime blood pressure, it's the hot topic and that's by itself is probably another 30 minutes to an hour of discussion. But I think that that's very important area of research. Dr Greg Hundley: Listeners, what a really wonderful discussion. And in this study from Japan of over 6,000 individuals treated for high blood pressure, those with 24-hour monitoring and exhibiting a rise in systolic blood pressure during the nighttime was associated with future cardiovascular events and an increase in the risk of heart failure. Moving forward from these experts, performing additional observational studies to confirm these findings and other populations, and perhaps a randomized trial, trying to target therapeutic interventions that would lower nighttime blood pressure may be warranted. Thank you Dr Kario and Dr Vongpatanasin. We wish you a great week and we look forward to catching you on the run next week. This program is copyright The American Heart Association, 2020.

Det er spesielle tider i verden, og det kan bli lenge til mer NBA på parketten. Vi i Time Out synes at tiden da er perfekt for litt topp 10 lister fremover. Vi starter med topp 10 point guards i NBA fra og med 1980. Stort sett harmoni fra Gnatt og Omland, men Barstad har tydelige issues med plasseringen til en av spillerne.

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And this is Dr Greg Hundley from VCU health, the Poly Heart Center in Richmond, Virginia. Well, Carolyn, this week's feature analyzed a pool cohort of all patients in partner one and partner two, both the trials and registries. Patients had severe aortic stenosis and were treated with TAVR or SAVR and then were analyzed with respect to the development of prosthetic valve endocarditis. But more to come on that later. Dr Carolyn Lam: Let me start by telling you about my picks from this week's journal. So the first one is a really interesting natural experiment. First, do you think that a short term visit to a location with severe air pollution increases the risk of cardiovascular disease? Dr Greg Hundley: Well, Carolyn, I would say yes. Dr Carolyn Lam: Greg, you're too smart. But let me tell you what these investigators did. So their co-corresponding authors, Dr Araujo from David Geffen School of Medicine and UCLA, Dr Zhu from UCLA Fielding School of Public Health, and Dr Qiu from College of Environmental Sciences and Engineering in Peking University. These co-corresponding authors and their colleagues did a natural experiment by collecting urine and blood samples from 26 healthy adult residents of Los Angeles before, during, and after they spent 10 weeks in Beijing during the summer of 2014 and 2015. Dr Greg Hundley: I am really excited to hear this. Carolyn, what did they find? Dr Carolyn Lam: So traveling from less polluted Los Angeles to more polluted Beijing induced pro oxidative and pro inflammatory effects, which reversed after returning to Los Angeles. This is also the first human study associating exposures to polycyclic aromatic hydrocarbons with changes in paraoxonase 1, enzymatic activity, and circulating levels of hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids. Cool, huh? Dr Greg Hundley: Absolutely. Carolyn, you did an awesome job. Very nice. Well, my article comes from the world of basic science and it's from Dr Philip Shaul at the University of Texas Southwestern medical Center. So Carolyn, in recent studies of obesity induced insulin resistance in mice with corroborating findings in human type 2 diabetics, this group, Shaul’s group, previously made the surprising discovery that the insulin resistance is driven by an altered post-translational modification in IgG that leads to enhanced activation of FCYR2B in endothelial cells. And as a result, there is an attenuation of insulin transcytosis across endothelial cells and delivery to skeletal muscle myocytes where up to 80% of glucose disposal usually occurs. Dr Carolyn Lam: Oh. Interesting, Greg. So what did the authors find in the study and how did these findings equate with obesity and hypertension? Dr Greg Hundley: Well, they found that hyposialyation of the Fc glycan on IgG is identified as a key contributing factor in obesity induced hypertension. And therefore low levels of IgG Fc glycan sialylation may identify individuals at greater risk of developing hypertension. In addition, the degree of sialylation of IgG may predict the relative response of an individual to any hypertensive therapy. Dr Carolyn Lam: Nice. So my next paper is from Dr Al-Lamee from Imperial College, London, and colleagues who studied the ability of a pre-randomization stress echocardiographic score to predict the placebo-controlled efficacy of PCI within the ORBITA trial. Now as a reminder, the primary results of the ORBITA trial showed us smaller than expected effect size of PCI in comparison with placebo in single vessel stable coronary artery disease on the primary end point of change in treadmill exercise time. Now in the current study, 183 patients underwent dobutamine stress echo cardiography before randomization, and they found that the degree of ischemia assessed by dobutamine stress echo cardiography predicted the placebo-controlled efficacy of PCI on patient reported angina frequency. Dr Greg Hundley: Hmm. Very interesting. So help me out again, Carolyn. What's the clinical importance of this? Dr Carolyn Lam: Ah, so this study really provides the first placebo-controlled evidence of an association between stress echo cardiography, ischemia, and the magnitude of placebo-controlled benefit attributable to PCI. And the greater the downstream stress echo cardiography abnormality caused by the stenosis, the greater the reduction in symptoms from PCI. That's the take home. Dr Greg Hundley: Oh wow. Very interesting. You know, especially we perform so many stress echo cardiograms. What a great relationship to unfold and present. Well, Carolyn, I'm going to walk through several other important publications in this issue of the journal. The first is from Dr Peter Eckman from the Minneapolis Heart Institute, and he provides an In-Depth review of veno-arterial extra corporal membrane oxygenation, or VA-ECMO, for cardiogenic shock and it's beautifully written for the busy clinician. Robert Platt, PhD, and colleagues discuss in an On My Mind piece the fact that those with adverse cardiovascular sequelae during pregnancy may require development of new cardiovascular risk prediction models. The hypertension or the diabetes that occurs during pregnancy, perhaps we need to incorporate that into our prediction models. Next. Our own associate editor Torbjørn Omland provides results in a research letter from the peace trial relating the relationship between smoking and high sensitivity troponin T levels. Dr Allen Sniderman from McGill University Health Center writes a letter to Welsh and Associates regarding their study of the UK bio bank database and measures of HDLC. A paper we discussed just a few weeks ago. Dr Derek Chew from the DCRI and Durham North Carolina has another EKG challenge for us. And Dr Tracy Hampton provides an updated news report regarding cardiovascular disease from several recently published articles in the world of basic science. And then finally Dr Thomas Krieg from the University of Cambridge has a nice piece regarding clinical implications of targeting succinate metabolism in ischemia reperfusion injury. Well, Carolyn, what a great slate, but I can't wait to get to that feature discussion related to prosthetic valve endocarditis. Dr Carolyn Lam: Me too. Let's go. Our feature discussion today is really the first paper that describes adjudicated evaluation of prosthetic valve endocarditis in patients with transcatheter and surgical aortic valve replacement. Very unique and valuable data from the partner's trial. I'm so pleased to have with us the corresponding author, Dr Wael Jaber from Cleveland Clinic as well as our associate editor, Dr Manos Brilakis from UT Southwestern. So Wael, very unique question. Could you please tell us how you went about doing this? And I suppose in this setting, the first question on everyone's mind is how did you make this diagnosis of prosthetic valve endocarditis? Dr Wael Jaber: Actually we saw this as an opportunity that probably we should never miss. I think this is one of the rarer instances where we can objectively not only look at SAVR data but also TAVR data. And over the past maybe seven years, eight years, we started getting here as a referral center patients with TAVR endocarditis for surgery. And we never thought we'd start seeing these weird organisms, different bugs. Of course this is a population that's frail or elderly, but we never had any idea if they behave similarly to SAVR or differently than SAVR in our previous experience with SAVR endocarditis. So we planned this actually about maybe five years ago, but we didn't have the data because you know the partner trials were undergoing another evolution by going to lower and lower risk population. So we pose this question about a year and a half ago to CRS by asking them, can you provide us with the data on all the endocarditis in partner. The idea was not only to answer one question but to answer multiple questions. So the first question was in the modern era, what happens in SAVR? All the SAVR endocarditis information we have so far as you will know has been from mainly single center studies or even when we learn about it from multiple centers sites, usually IN European studies, the Swedish registry, the Danish registry, and these are usually limited by the fact that there are a multicenter. The adjudication is at the site what endocarditis happened. So that was the first question. Then the second issue for us was, does TAVR, because of the unusual access to the heart and the fact that we dilate the valve, post dilate the valve, their paravalvular AI, they could be micro-fractures of the refis. This is provide a different opportunity for these bugs to form on the valve, and do they behave differently? And the third question was, is there any difference between SAVR and TAVR incidence of endocarditis? And bugs. And the final question was what happens to patients when they develop endocarditis in the current decade. Do they do well? Especially for septic endocarditis or do they succumb to their illness? And also this is how we came up with a strategy to answer all these questions. Dr Carolyn Lam: Very nice. So Wael, could you just expand a little bit more about how the diagnosis or adjudication of prosthetic valve endocarditis was done? And then tell us please, what did you find? Dr Wael Jaber: All the partner patients, the records were sent to a central place. So the ECHOS first were educated at central places. We were one of those centers. Other places were Columbia University, MedStar and Quebec, the group in Quebec. So all the ECHOS were adjudicated centrally. So that's first, as far as from the echo side of calling it endocarditis or not. On the clinical side, again, all the records and the forms were sent to a central adjudication committee, CDC group. We served at the Cleveland Clinic as the CDC for most of these trials and actually even for the current trials. So they were sent and they were adjudicated according to the Duke criteria. Which is, you know, the most, probably, reliable way still today to adjudicate these. And then there was the CDC and the echo core labs were separate. So the people who have information from the CDC did not have access to what's going on in the core lab and vice versa. So these were independently adjudicated as far as echocardiographic evidence and clinical evidence. And then they were fed into it. So by the end, when you hold it on a Duke criteria endocarditis, the echo was fed after the fact, not before. So this is in general how it happened. So all the events were educated centrally, not at the site. And the ECHOS, the same thing, were adjudicated centrally. Dr Carolyn Lam: Fantastic. And I would love to hear the results. Dr Wael Jaber: The first question was, what's the incidence of endocarditis? And we decided because of the way these trials were done, to report the incidents as you would see in the results section, to report the incidents of endocarditis per 1000 person year because of the imbalances in follow up and the competing risk for death from other reasons. So we found in general that the incidents of endocarditis was 5.2 endocarditis events per 1000 patients per year in the TAVR side and 4.1 in the SAVR side with a non statistically significant difference. More importantly, we found out that once you develop endocarditis, unfortunately most of these patients succumb to the illness and are dead after the diagnosis. So the risk of dying after developing endocarditis is 4.4 times higher than patients who did not have endocarditis in the trials. In all the trials. Now there's some caveats here. First, these are trials with different patient populations, as you well know. Starting with partner with the inoperable patients moving on to the most modern S3 trial, which was on the lowest kind of side of population. So we have totally different population groups. Some of them had prolonged hospitalizations before and after, so this should be taken with a little bit of caution. However, if you look at some of the individual trial data, we found that incidents of endocarditis at least have a trend towards a reduction of incidence of endocarditis over time going from partner, the initial experience with partner, all the way to the modern era. Dr Carolyn Lam: That is so great. Manos, you know, as an interventional cardiologist yourself, could you tell us how important these results are? Does it affect your practice? Dr Emmanouil Brilakis: Thanks again, Carolyn. I would like to congratulate Wael for a phenomenal paper. I think it's a very timely study and addresses one of the common concerns there is about whether TAVR does predispose people to more risk for endocarditis. Although again, the opposite grade was kind of low at 0.5% a year. I think this may be a little more than people are commonly seeing in the setting of TAVR, and I think the paper is a good reminder that this is something we should always be mindful and watching. Although typically we'll discuss with the patient about the risk of stroke or access complications, but the risk of infection may not be as well emphasized. And based on this one question I would have is about what can we do if there is something that could potentially lower that risk? I understand the limitations of retrospective study, but are there any recommendations that you have based on the study? Should give more aggressive antimicrobial therapy? Any other biotic prophylaxis or anything else that can be done to reduce the risk of endocarditis in those patients? Dr Wael Jaber: Actually this is the question we raised. Unfortunately we did not. So the guidelines did not catch up with what we know. So if you look right now, like I was reviewing this paper that came up last month from the Swedish Registry for Endocarditis, it came out in Europe in the European Heart Journal, and one of the questions they raised is how to address, in the editorial, how to address the risk of endocarditis and prophylaxis in this population. There are no standards for that. This is one aspect of it. We need first an update of the guidelines of how to address this issue. The second question is we do not have any idea, unfortunately, about duration of antibiotics. How the antibiotics prophylaxis were given before the procedure, like as we do right now commonly in surgery, and after the procedure in these patients. We do not know that. Like right now, at least at our center, if you go in for aortic or mitral valve surgery or any valve surgery, you have to have a dental clearance before you start, before you go to surgery. I don't know if this was rigorously applied in the setting of TAVR, and I think it would be a good idea to apply it to make sure that there are no dental, phosphide or potential infections and things like that. So I think it's a multi-front battle to get these patients to the lowest risk possible. I don't think there's one single silver bullet here. Dr Emmanouil Brilakis: So thanks again, Wael for addressing this. I agree that there's a lot of information to be gained understanding the intricacies of endocarditis prophylaxis. And building on this, let's say another patient develops endocarditis as you've shown in your 170 patients in the study. It was fascinating that staph aureus was actually less common than it was for surgical valves, which has been shown in other studies as well. So you think this affects the choice of the biotic prophylaxis? And then also if the patient develops endocarditis, I understand many people who are not candidates for surgery, but from the ones who did actually undergo surgery, what are the outcomes encouraging? Dr Wael Jaber: This is a fascinating question actually. This is one of the reasons we had... There was a delay for us in getting the paper out from when we presented it as an abstract at TCT a year and a half ago, is we didn't know. We wanted to answer that question. The second part of the question is how many patients went to surgery? And unfortunately, very few patients. So less than a handful of patients end up going to surgery. And we do not know why. So this is the dilemma here. Is why the rate of referral to surgery for redo surgery was very low. Was it because these patients were the sickest of the sick? Maybe it is because we waited too long and we did not treat them the same way. We should have treated prosthetic valve endocarditis, which is surgery to be offered as soon as possible because there's no really antibiotic cure for that. So we do not have the answer for that because these very few patients went to surgery and actually I think of those who went to surgery, even the mortality there even was similar to people who did not go to surgery. But we cannot speculate on that because the very few patients. As far as the bug involved, I think this could be a reflection of the antibiotics given at the time of the procedure, so probably we're covering that very well. But if you notice from the paper, most of the infections happen more than 30 days after the procedure. Whether this is something that was acquired because these patients are more likely to end up in the hospital again for other reasons, whether these patients had endocarditis because they have more instrumentation down the road... Remember this is a population in general above the age of 65 which would require colonoscopies, frequent urinary tract issues, and other procedures. So we know that we're covering very well, at least I can speculate, we're covering very well for the first 30 days because very few patients had endocarditis right after the procedure, but we're not covering probably after the 30 days. And that remains to be studied. And the worrisome thing is to try to treat these patients with prophylactic antibiotics for a long time and then end up with bug resistance and things like that. Now the CDC issued a big warning about this yesterday. I am not comfortable to speculate from this small number of patients on how to treat for prophylaxis, but I'm comfortable to say probably patients should be sent to surgery as soon as possible after developing endocarditis, especially prosthetic valve endocarditis because the outcomes are dismal. Dr Emmanouil Brilakis: And do you think... Let's say patient is not a candidate for surgery and gets endocarditis, and I presume they get into prolonged therapy. There were some patients like this that did okay, right? So there is some hope even for those patients. Dr Wael Jaber: I feel like I'm the cup half full here because if you look at the mortality curves here, we're talking about north of 95% death in this population. So the people who survive this must be very few people survive. So probably about seven patients who survive. So the mortality was 96% at six months versus 46%. So there are very few people who survived that event. Maybe I should go back now and figure out what was the quality of life after survival. So I don't think the picture we have right now is very rosy as far as the way we're managing endocarditis. Dr Carolyn Lam: Manos, I'm going to give you the final parting words from this very interesting discussion. I mean what do you think are the take home messages and future directions from here? Dr Emmanouil Brilakis: I agree that this is a phenomenal landmark study and my key takeaways are the same ones that Dr Jaber presented before. But the main thing is, on the consent process, who can tell the patients there is about 0.5% per year. So it's not zero, but it's very high either. The second thing is that this choice between TAVR versus SAVR, that should not have to do with the risk of infection because as it was shown very convincingly, it was very similar to the two groups. And number three that everything possible should be done to prevent this because if you do get infection, the outcomes are not very good. Dr Carolyn Lam: Thank you so much Manos, Wael. Thank you so much audience for joining us today. You've been listening to Circulation on the Run. Tune in again next week. This program is copyright American Heart Association 2019.  

Flixbus hat die Mobilitätswelt verändert: Auf dem Fernbus-Markt hat das Unternehmen einen Marktanteil von 95 Prozent. Gerade ist das Start-up in den USA gestartet. Und nun nehmen sich die drei Gründer weitere Märkte vor. Dafür hat Flixbus im Sommer das nötige Kapital eingesammelt, in einer der größten Finanzierungsrunde, die je ein deutsches Start-up erhalten hat. Was Flixbus für die nächsten Monate plant, welche weiteren Märkte für das junge Unternehmen interessant sind und ob es nach Flix-Bussen und Flix-Trains auch irgendwann Flix-Planes geben wird, erklärt Flixbus-Mitgründer und CEO Jochen Engert diese Woche bei Handelsblatt Disrupt. Die reine Zahl von Patenten sagt wenig über die Innovationsstärke von Unternehmen aus. Viel wichtiger ist die Frage: Wie wertvoll die Patente sind. Das Bonner Unternehmen Patensight hat dafür ein spezielles Verfahren entwickelt. Wie das funktioniert, warum die Daten Konzerne, Investoren und politische Institutionen aus aller Welt nutzen, das erklärt Patensight CEO Nils Omland.

In der heutigen Folge schaue ich mit dir in den Kopf von Jan Omland. Gemeinsam finden wir heraus, wer er wirklich ist und wie Jan den Zugang zu sich selbst, seinen Emotionen und seiner wahren Vision gefunden hat. Wer die Folge mit Claudia Omland gefeiert hat, kann sich heute freuen. Denn Jan ist ihr Mann und wir können die Themen aus der Podcastfolge mit Claudia aus einer anderen Perspektive sehen. Seit 2010 stärkt Jan Männern den Rücken. Sex spielt in Beziehungen eine große Rolle und leider SCHEITERN immer wieder BEZIEHUNGEN an genau diesem Thema. Erfüllte und REGELMÄßIGE SEXUALITÄT ist in seinen Augen etwas wunderbares. Sein persönlicher Herzenswusch: Er möchte Männer für LEIDENSCHAFTLICHE BEZIEHUNGEN begeistern! Der Blick in die Augen eines Mannes, der endlich seine Traumbeziehung führt und regelmäßig leidenschaftlichen Sex hat, DAS ist es was ihn antreibt. Mehr über Jan und über diese Themen erfährst du jetzt! Viel Spaß! :-) __________ Was hat es dich bisher gekostet, so zu sein, wie andere es wollen? Es wird Zeit JA zu dir zu sagen. Für dich, deine Wünsche und deine Sicht der Welt einzustehen, auf dem Emotional Experience Day. Mit dem Code „rausausdeinemkopf“ bekommst du 25% Rabatt: Sichere dir jetzt dein Ticket: http://bit.ly/EmotionalExperienceDayPodcast Finde heraus, welches Emotionale Schutzprogramm du besitzt und wie dich dieses blockiert. Mache jetzt den Test: https://yvonneschoenau.com/kaktus/ Hier kommst du zum KOSTENLOSEN Ebook: https://yvonneschoenau.com/#download _____ Lass uns gemeinsam diese Welt verändern: Facebook: https://www.facebook.com/YvonneSchoenau.Training/ Instagram: https://www.instagram.com/yvonneschoenau/ LinkedIn: https://www.linkedin.com/in/yvonne-sch%C3%B6nau-2a581665/?originalSubdomain=de YouTube: https://www.youtube.com/channel/UC3g67dN26I14IzHodhKVKoQ __________ Hier findest du mehr zu Jan Omland: Zum Online Kurs "Länger durchhalten": https://mitglieder.61minuten.de/ Jan hilft dir zurück in deine Kraft zu finden, wenn du ihm eine Email an jan@61minuten.de mit Betreff „Yvonne Schönau“ schreibst. __________ - Instagram https://www.instagram.com/winterjan/ - Youtube: https://youtube.com/61MinutenSex

In der heutigen Folge schaue ich mit dir in den Kopf von Claudia Omland. Gemeinsam finden wir heraus, wer sie wirklich ist und wie Claudia den Zugang zu sich selbst, ihren Emotionen und ihrer wahren Vision gefunden hat. Claudia ist Expertin für Liebe & Lust ohne Limit. Über 350 Frauen und über 100 Männern hat Claudia Omland in den letzten 3 Jahren dabei unterstützt sich jenseits von Scham und Schuld eine ganz persönliche sexuelle Identität zu erschaffen und Beziehungen zu führen, die kein Wachstumslimit haben. Sie wurde ausgebildet in jahrtausende alten tantrischen Techniken, sowie modernen, international renommierten Beziehungscoaching- Methoden, um den Status Quo in Liebe und Lust von Frust auf grenzenlos zu steigern. Dabei war ihr eigenes Liebesleben nicht immer auf dem Status grenzenlos. Schon als Jugendliche hatte sie eine unheimlich große Faszination für Sex und die Tiefe der damit verbundenen Emotionen. Ein relativ freies Entdecken der eigenen Sexualität wurde im Laufe der Zeit von gesellschaftlichen & familiären Stigmen überlagert. Scham, Schuld die Angst, als Schlampe abgestempelt zu werden haben sie soweit von ihrer eigenen Sexualität entfernt, dass sie 2012 in ihrer Lebenskrise ihren Orgasmus verloren hat. Ihr war sofort klar, dass das nur auf die Spitze getrieben hatte, wie weit sie aus dem Kontakt mit sich selbst und vor allem ihrer Identität, als Frau gekommen war. Mit der Frage, „wer bin ich als (sexuelle) Frau?“ landete sie in einem 2 jährigen tantrischen Persönlichkeits-Training, das alles was sie über Männer, Frauen, Sex und Liebe glaubte völlig auf den Kopf stellte. Schon während dieser Trainings setzte sie sich selbst radikalen Experimenten aus, um herauszufinden, was für sie selbst in Bezug auf Sex wirklich stimmt. So hat sie zum Beispiel als Escort gearbeitet, um herauszufinden, ob es wirklich erniedrigend ist, sich für Sex bezahlen zu lassen. Heute ist Claudia selbstständiger Coach und zeigt vor allem Frauen, wie sie ihre Weiblichkeit voller Stolz als größtes Geschenk mit in die Beziehung zu einem starken Mann nehmen und so auf Augenhöhe etwas erschaffen, das viel größer ist, als die Summe seiner Teile. Über diese Themen sprechen wir auch im heutigen Podcast. Viel Spaß! :-) __________ Was hat es dich bisher gekostet, so zu sein, wie andere es wollen? Es wird Zeit JA zu dir zu sagen. Für dich, deine Wünsche und deine Sicht der Welt einzustehen, auf dem Emotional Experience Day. Mit dem Code „rausausdeinemkopf“ bekommst du 25% Rabatt: Sichere dir jetzt dein Ticket: http://bit.ly/EmotionalExperienceDayPodcast Finde heraus, welches Emotionale Schutzprogramm du besitzt und wie dich dieses blockiert. Mache jetzt den Test: https://yvonneschoenau.com/kaktus/ Hier kommst du zum KOSTENLOSEN Ebook: https://yvonneschoenau.com/#download _____ Lass uns gemeinsam diese Welt verändern: Facebook: https://www.facebook.com/YvonneSchoenau.Training/ Instagram: https://www.instagram.com/yvonneschoenau/ LinkedIn: https://www.linkedin.com/in/yvonne-sch%C3%B6nau-2a581665/?originalSubdomain=de YouTube: https://www.youtube.com/channel/UC3g67dN26I14IzHodhKVKoQ __________ Hier findest du mehr zu Claudia Omland: - Website: claudiaomland.com - Email: claudia@claudiaomland.com - Gewinne 1 von 10 20 Minuten Coaching gratis im Wert von 500EUR mit Claudia und ihr löst gemeinsam die größte Blockade: https://calendly.com/lovecoachclaudia/freefueryvonnefans

Dr Carolyn Lam:                Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam:                So Greg, have you ever wondered what is the clinical significance of exercise induced cardiac troponin eye release with regards to mortality and cardiovascular events? Dr Greg Hundley:             Well, being a runner, and you are too, I actually have wondered about that. Dr Carolyn Lam:                Well guess what? I'm not going to tell you the answer because you're going to have to wait for our feature discussion coming right up after we chat about a few wonderful papers in this week's issue. And I want to start. So the first paper I chose really sought to discover new and effective drug treatments for ischemic stroke. And it did this by integrating genetic and proteomic data through Mendelian randomization analysis. Dr Greg Hundley:             So Carolyn, what is Mendelian randomization analysis? Dr Carolyn Lam:                Well, I would have loved to quiz you on that, but since you already asked me, I'll tell you. So Mendelian randomization is a statistical genetics framework that's used to assess causality between an exposure and an outcome. So similar to how randomized controlled trials randomly allocate an intervention to test its causal effect on an outcome. Well, Mendelian randomization represents a sort of natural randomized control trial that leverages the random allocation of exposure influencing genetic alleles.                                                 Now previously, this technique of Mendelian randomization was applied in a hypothesis driven manner to assess causality of selected biomarkers on stroke risk, for example. However, there has been no systematic scan of the human proteome for novel causal mediators of stroke. And beyond drug target prioritization, Mendelian randomization can actually also be applied to predict target mediated side effects to reveal unanticipated adverse effects and opportunities for drug re-purposing. Hence, in the current paper, the authors led by Dr Paré from Hamilton Health Sciences, McMasters University and colleagues, use Mendelian randomization to firstly systematically screen 653 circulating proteins to identify novel mediators of ischemic stroke subtypes.                                                 Secondly, examine the relationship between identified biomarkers and the risk of intracranial bleeding. And thirdly, predict target mediated side effects through phenome wide analysis. They found that among these 653 proteins, seven were causal mediators of ischemic stroke, including two established targets, apolipoprotein allele and coagulation factor 11. As well as two novel mediators of cardioembolic stroke, which were scavenger receptor class A5, or SCARA5, and tumor necrosis factor weak inducer of apoptosis.                                                 They further showed that targeting SCARA5 was predicted to also protect against subarachnoid hemorrhage with no evidence of it for side effects. Some biomarkers mediate at risk of multiple non-stroke disorders. So in summary, integrating genomic, proteomic and phenomic data through Mendelian randomization facilitated discovery of drug targets and their side effects. Their findings provide confirmatory evidence for pursuing clinical trials of coagulation factor 11 and apolipoprotein allele. Furthermore, SCARA5 represents a new therapeutic target. Neat, huh? Dr Greg Hundley:             You bet. Well, my basic paper, Dr Carolyn Lam, focuses on the border zones of infarcts. And it comes to us from Vincent Christoffels from the Academic Medical Center in Amsterdam. So surviving cells in the post infarction border zone is subjected to intense fluctuations of their microenvironment. We can imagine that. And recently border zone cardiomyocytes have been specifically implicated in cardiac regeneration. Here in this study, the investigators define their unique transcriptional and regulatory properties and comprehensively validated new molecular markers, including NPB or encoding B-type natiriuretic peptide after infarction.                                                 So, in the study, transgenic reporter mice were used to identify the NPB positive border zone after mitochondrial infarction, and transcriptome analysis of remote border and infarct zones, and of purified cardiomyocyte nuclei was performed using some RNA sequencing. Top candidate genes displaying border zone spatial specificity were histologically validated in ischemic human hearts. So like these great papers we have in basic science, there is a fundamental mouse and then human subject validation. Dr Carolyn Lam:                 Nice. A lot of work. So what did they show? Dr Greg Hundley:             So Carolyn, the investigators identified the border zone as a spatially confined region transcriptionally distinct from remote myocardium. The transcriptional response of the border zone was much stronger than that of that remote ventricular wall involving acute downregulation of mitochondrial oxidative phosphorylation, fatty acid metabolism, calcium handling and sarcomere function, and activation of the stress response program.                                                 Analysis of infarcted human hearts revealed that the transcriptionally discrete border zone is conserved in humans and led to the identification of novel conserved border zone markers including NPBB and a whole list of others. So in conclusion, cardiomyocytes in a discrete zone bordering the infarct switch gene expression programs, this post switch program is conserved between mouse and humans, includes the NPPB expression, which is required to prevent acute heart failure after infarction. Dr Carolyn Lam:                Wow, really interesting. Well, my next paper is also really just novel information, and it's a promising clinically-relevant approach for immune modulation in transplantation medicine. And that is by selectively targeting notch one. Dr Greg Hundley:             Tell us a little bit about notch signaling. Dr Carolyn Lam:                Well, I'm glad you asked me before I asked you again because notch signaling is a highly conserved pathway, pivotal to T cell differentiation and function, rendering it a target of interest in efforts to manipulate T cell mediated immunity. Now this is relevant in transplantation since, despite advances in immunosuppression, long-term outcomes remain suboptimal and is hampered by drug toxicity and immune mediated injury, the leading cause of late graph loss.                                                 So, the development of therapies that promote regulation while suppressing effector immunity is imperative in improving graph survival and minimizing conventional immunosuppression. In today's paper, Dr Riella and colleagues from Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts investigated the pattern of notch one expression and effector and regulatory T cells in both murine and human recipients of a solid organ transplant. They further examine the effect of notch one receptor inhibition in full murine cardiac and lung transplant models as well as in a humanized skin transplant model, and also in T regulatory cells. They found that notch one is a potent novel target to modulate aloe immunity. Blockade of notch one signaling prolongs allograph survival and enhances tolerance in animal transplant models in a regulatory T-cell dependent manner.                                                 So, in summary, these data suggests that notch one signaling pathway is a potentially clinically relevant target to control effector function and promote immune regulation after transplantation. Dr Greg Hundley:             Oh wow. A lot of intense work, and I learned about notch pathways. I am going to switch and talk about a clinical situation that's really emerged over the last five years, particularly in our scientific literature. And that's tricuspid regurgitation. And this paper comes to us from Dr Jeroen Bax from Leiden University Medical Center in the Netherlands. So in patients with moderate and severe tricuspid regurgitation, the decision to intervene is often influenced by right ventricular size and function. And right ventricular remodeling in significant secondary TR however been under explored. And so in this study the investigators characterize right ventricular remodeling in patients with significant secondary tricuspid regurgitation, and they investigated its prognostic implications. Dr Carolyn Lam:                 Indeed, very important topic. So please tell us what they found. Dr Greg Hundley:             Okay, so they use transthoracic echo-cardiography, and it was performed in 1,292 patients with significant secondary tricuspid regurgitation with patients having an average or median age of 71 years. Half were men, half were women. They had four patterns of right ventricular remodeling, and they were defined according to the presence of RV dilation with the tricuspid annulus of greater than 40 millimeters and RV systolic dysfunction. So pattern one was normal RV size and normal RV systolic function. Pattern two was a dilated RV with preserved systolic function. Pattern three, normal RV size with systolic dysfunction. Pattern four was a dilated RV and systolic dysfunction.                                                 So the primary end point was all caused mortality and event rates were compared across these four patterns of remodeling. So what did they show, Dr Carolyn Lam? The five-year survival rate was significantly worse in patients presenting with either pattern three or pattern four remodeling compared to pattern one, which was normal. And they were independently associated with poor outcome in multivariable analysis. Thus, in patients with significant secondary tricuspid regurgitation, patients with RV systolic dysfunction have worse clinical outcomes regardless of the presence of the magnitude of RV dilation. So really helps us as we're trying to decide what going to do with that tricuspid valve and modifying the severity of tricuspid regurgitation. Very nice work. Dr Carolyn Lam:                 Yeah. Very interesting. Now let's get to our feature discussion. Dr Greg Hundley:             You bet. Dr Carolyn Lam:                Our feature discussion today is all about cardiac troponin increases after endurance exercise. Is it a new marker of cardiovascular risk? What should we think of it? Is it associated with cardiovascular events? Now I know many of us has thought of this many times and we're going to get some beautiful answers with today's feature paper. I'm so glad to have the corresponding author, Dr Thijs Eijsvogels, from Radboud Medical Center that's in Nijmegen. And I also have our associate editor and editorialist for this paper, Dr Torbjørn Omland from University of Oslo. So welcome gentlemen, and if I could please start. Thijs, I think a good place to start would be for you to tell us about this four-day march of Nijmegen. Tell us about that and how your study builds on that. Dr Thijs Eijsvogels:           The Nijmegan four-day marches is actually the largest walking march in the world, so it's hosted every year in July in the Netherlands, and about 45,000 people walk for four consecutive days. And this gave us the opportunity to collect some research data during this great exercise event. What we did over the past couple of years is that we've collected blood samples and participants of this Nijmegan marches. We did a before exercise and also directly after exercise. Within those blood samples we determined the concentration of cardiac troponin eye, which is a marker of mitochondrial damage. And what we subsequently did is that we followed this group of walkers over time and we collected data about diverse events that occurred, and also whether they survived or whether they died over time. Dr Carolyn Lam:                Thijs, it's such a clever setup for a study. Now give us some idea though. We're saying walking for four days; how many kilometers is covered? And when you say before and after your troponin sampling, give us an idea of how many hours of walking that would be. Because I believe you did it only on the first day, right? Dr Thijs Eijsvogels:           Yeah, that's correct. So the distance that they must cover is dependent on sex and on age. So for example, if you're a male older than 50 years old, you can walk 30 kilometers per day, but then for four days in a row. But if you are a young individual like me, then you have to cover 50 kilometers per day. So that's a lot more. Typically, they walk about four to five kilometers per hour. So that means that if you walk the shorter distances then you are done within six to seven hours of walking. But if you walk for a longer period of time, then you need 10, 11, and sometimes even 12 hours to complete the distance. Dr Carolyn Lam:                Okay, there you heard it everybody. So we've got a stress test of a mean, I'm reading from your paper, 8.3 hours of walking at almost 70% of maximum heart rate. So that's really cool. Now before you go on further too, tell us a little bit about the population because everybody's wondering, oh no, does this apply to me? Dr Thijs Eijsvogels:           So the population participating in this walking event, I would almost say it's about a representation of the general population. So we have very healthy and very trained individuals. So you could say athletes. But we also have people with cardiovascular disease or cardiovascular risk factors. And even obese individuals. So it's a very mixed population, and it's not like the typical athlete population that you see at a runner’s event, for example. Dr Carolyn Lam:                Great. That's important. So now with that backdrop, please tell us your main findings. Dr Thijs Eijsvogels:           We measured this cardiac troponin and eye concentration, and we determined the number of individuals that were above the clinical threshold, which is the 99 percentile. And then we've compared the event rate. So major at first cardiovascular events and mortality with those walkers who had a cardiac troponin above the 99 percentile and those below it. And then we found that it was way higher in the walkers with the high troponin concentration. So they had an event rate of 27%, whereas the reference group they only had an event rate of 7%. So that was quite a marked difference. Dr Carolyn Lam:                That's huge. So first data of its kind and it's so scary because I think, Torbjørn, as you discussed in your editorial, a lot of us have sort of excused the rises in troponin that we know have been reported at the marathons and all that. So how do you put it all together, Torbjørn? what are your thoughts? Dr Torbjørn Omland:      So I would just like to congratulate Dr Eijsvogels with a very interesting article. And the findings are, as you say, very novel and significantly enhances our understanding of the prognostic implications of exercise induced increase in cardiac troponins. That transient increase in cardiac troponin concentrations may occur in many circumstances, and it's usually considered to reflect acute mitochondrial injury. And thus it has been considered to reflect harmful pathophysiological processes.                                                 But there has to be in one notable exception and that has been the rise in cardiac troponin after endurance exercise, which has commonly been considered a benign phenomenon. But until this study, definitive data relating post exercise troponin concentrations, or the magnitude of the cardiac troponin response following exercise have been lacking. So with Dr Eijsvogels' study we now have clear data showing that these are associated with increased risk. Dr Carolyn Lam:                That's amazing. So thank you for that in context. Thijs, do you agree? I mean that is a beautiful summary, but what is the take home for listeners? What should we be thinking about now first pertaining to our own exercise I suppose, but also then how do we interpret this clinically? Dr Thijs Eijsvogels:           I think that Dr Omland made a great point. So for a long period of time we thought that it wasn't a benign phenomenon, that everybody had those increases in cardiac proponents following exercise and also the pattern that was way different from what we see in clinical populations. So we thought, it's just a physiological phenomenon and it doesn't hurt the heart. But clearly our study now shows that there is an association between high post-exercise troponin concentrations and clinical outcomes. So this is an important finding.                                                 And basically there are two hypothesis I guess that could explain those findings. So first of all, it could be that participants with higher troponins have subclinical or underlying disease. And due to this walking exercise, that could be a stress test for the heart. And then those with vulnerable hearts, they demonstrate a greater increase in cardiac troponins. On the other hand, we should also acknowledge the hypothesis that even though it's moderate intensity exercise, it could be some damage to cardiomyocytes. And those individuals with the greatest or the highest troponin concentrations, they could have more cardiomyocyte damage compared to individuals with lower troponin concentrations. And if you then have repetitive exposures to exercise bouts, it could be harmful in the long run as well. Dr Carolyn Lam:                And so, Torbjørn, you discuss this along with several different mechanisms by which troponin could be increased. Do you have anything else to add to that? Dr Torbjørn Omland:      No, I think it's very right what the Dr Eijsvogels point out. So on one hand we can consider this like a stress test. And there are some data suggesting that that could be the main effect, in that those who had the higher baseline troponin in the trifocal study also demonstrated the highest increase. So in one way you could consider this as a long-term exercise test. Of course that makes it less applicable in clinical practice. So because we can't have exercise test that last for so many hours, but I think that should be an impetus to have more standardized tests that could be applied to the clinical practice. Dr Carolyn Lam:                There's also a comment that you made about the kind of troponin tests that we're applying here, that people should understand that we're using the high sensitivity ones, right? Is that correct? Dr Torbjørn Omland:      Actually, it is not the high sensitivity, but it is a contemporary essay, but it had quite good sensitivity even though it is not classified as a high sensitivity test. Dr Carolyn Lam:                Thank you for clarifying that. I know you made a point about that, that we should know what kind of tests we're talking about. The other thing is what are the remaining unanswered questions then? Like you said, we can't do an eight-hour walking test. Should we be measuring troponins now in our exercise stress? Which kinds? What time? No, it's not time yet? What are the next steps? I'd like to hear from both of you, actually. Dr Thijs Eijsvogels:           First of all, indeed it's not possible in clinical practice to do an eight-hour tests whatsoever. But I think that it could be interesting to explore that maybe with some small modifications to current stress tests, if we do it maybe on a little bit lower intensity. For example, moderate intensity exercise, but we do it for a fixed amount of time and then collect blood sample to determine a highly sensitive correct proponents., then maybe also the Delta, so the increase in proponents could be predictive sign of underlying disease. Because what you see in studies that have been published so far is that the duration of most stress test is too short to induce any substantial changes in aortic troponin concentrations. So I think if we modified a protocol a little bit, we can see greater increases in cardiac troponins, and that could provide us with more information, of course. Dr Torbjørn Omland:      I completely agree. And I think like all great studies, this study raises many new questions, and of course how we should use this clinically is very important one. And as such Eijsvogels pointed out, standardized tests will be required. And I think how much the Delta information we get from measuring the Delta to just the baseline should be one topic for future studies.                                                 And then of course we know that the cardiac troponin increase is a risk factor. But what we also would like to know is whether the at risk is modifiable in some way. So there are some studies that have suggested that increasing your physical activity over time can actually decrease your sort of chronic cardiac troponin concentration. And it would be interesting to see whether increased physical activity over time will also reduce the increase that you observe after a stress test like in Nijmegan march. Dr Carolyn Lam:                That's such great points. And if I could add too, not to forget that the study population here, would I be right to say the majority are middle aged individuals and they do have cardiovascular risk factors or even prior cardiovascular disease in a sizeable proportion? So to what extent these findings generalized to a really, like the young, athletic, competitive, athletic population? Could you comment on that Thijs? Dr Thijs Eijsvogels:           I think that's a very good point, that we cannot compare this population where the fit population competing in running events or cycling events or triathletes or whatsoever. So I think we definitely need follow up studies that reproduce our findings in different cohorts with different training modalities, with different age categories, and so on. So that's definitely a topic of interest for future studies. Dr Carolyn Lam:                Thank you so much. I mean, you've inspired me on so many levels. You've been listening to Circulation On The Run. Don't forget to tune in again next week. Dr Carolyn Lam:                 This program is copyright American Heart Association 2019.  

! es wird pikant !  ! es wird ehrlich !  ! es wird geil !  : D Dieses Interview hat mir ultra viel Spaß gemacht, ich selbst hab total viel Neues erfahren und freue mich über deine Meinung (bit.ly/Feedback-HappyFinanceLife). Was ist Sex für dich? Wie definierst du Orgasmus?  Und was möchtest du noch alles lernen?  Inhalte der Folge: [4:30] Why your pussy makes money :D [19:00] So wird eine erfüllte Paarbeziehung möglich [27:00] Wie du deinen Mann in seiner Männlichkeit stärken kannst [38:30] Tipps um im Alltag mehr weibliche Qualitäten zu leben [50:00] Kurzeinführung in die Tantra Lehre Empfehlungen aus der Folge: Seminare - tantra.de Buch - Zeit für Weiblichkeit Buch - Orgasm unleashed Links zu Claudia: claudiaomland.com fb.com/LoveCoachClaudia Persönliche Facebook-Page Links zu Desirée: instagram.com/Desiree.Benke fb.com/Desiree.Benke iTunes &Website  --- Send in a voice message: https://anchor.fm/happy-finance-life/message

Correne is a true homesteader and Traditional Western Herbalist.  Her passion for living a life that is sustainable for her family and mother earth shines in this podcast.  She also tells me about her decision to leave vegetarianism behind.  Very interesting. Please remember to Subscribe! Correne Omland on Instagram Correne Omland Web Site

Walter has a solution to avoiding government shutdowns in the future and shows how the media can manipulate your view of the issues.

Walter has a solution to avoiding government shutdowns in the future and shows how the media can manipulate your view of the issues.

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.                                                 Does measuring baseline BNP add prognostic information in patients undergoing revascularization for left main coronary artery disease? Well, to find out the answers, you have to stay tuned and listen up for our feature discussion coming right up, after these summaries.                                                 The first original paper this week reports a new role for bone morphogenetic protein 9, or BMP9, as an endogenous inhibitor of cardiac fibrosis. Now, we are familiar with transforming growth factor beta-one, or TGF-β1, as a promoter of cardiac fibrosis. TGF-β1 also activates counterregulatory pathways that serve to regulate TGF-β1 activity in heart failure. BMP9 is a member of the TGFβ family of cytokines and signals via the downstream effector protein Smad1.                                                 In the current paper from first author Dr Morine, corresponding author Dr Kapur, from Tufts Medical Center in Boston, and their colleagues. The authors examined BMP9 expression and signaling in human cardiac fibroblasts and human subjects with heart failure. They utilized the thoracic aortic constriction–induced model of heart failure to evaluate the functional effect of BMP9 signaling on cardiac remodeling. The authors’ results identified a novel functional role for BMP9 as an endogenous inhibitor of cardiac fibrosis due to LV pressure overload. They further showed that treatment with either recombinant BMP9 or inhibiting a high affinity receptor for BMP9 known as endoglin promoted BMP9 activity and limited cardiac fibrosis in heart failure. Thus, this provides a potential novel therapeutic approach for patients with heart failure.                                                 The next paper shows that endothelial C-type natriuretic peptide, or CNP, regulates microcirculatory flow and blood pressure. First author, Dr Špiranec, corresponding author Dr Kuhn, and colleagues from University of Würzburg in Germany analyzed whether vasodilating response to CNP changed along the vascular tree. In other words, whether the guanylyl cyclase–B receptor was expressed in microvascular types of cells. The authors used novel gene-modified mouse models to show that guanylyl cyclase–B cyclic GNP signaling in parasites diminished microcirculatory resistance and arterial blood pressure. In contrast, endothelial, or macrovascular smooth muscle cell guanylyl cyclase–B signaling was not involved. This indicated that CNP participated in the local cross talk between endothelial cells and parasites, thus playing an important role in the maintenance of normal microvascular resistance and blood pressure. Thus, pharmacological augmentation of endogenous CNP signaling in parasites may provide a useful therapeutic tool to combat increased vascular resistance and hypertension.                                                 Has the rapid and exponential growth in transcatheter aortic valve replacement, or TAVR, demand overwhelmed capacity, thus translating to inadequate access and prolonged wait times? Well, the next paper provides some answers. First author, Dr Elbaz-Greener, corresponding author Dr Wijeysundera, from University of Toronto, evaluated temporal transient TAVR wait times and the associated clinical consequences in their population-based study of all TAVR referrals from April 2010 to March 2016 in Ontario, Canada. Their study cohort included 4,461 referrals, of which 50% led to a TAVR, 39% were off-listed for other reasons, and 11% remained on the wait list at the conclusions of the study.                                                 For patients who underwent a TAVR, the estimated median wait time in the post reimbursement period stabilized at 80 days and has remained unchanged. The cumulative probability at 80 days of wait-list mortality was 2% and of heart failure hospitalization, 12%, with an increase in events with increased wait times. Thus, post reimbursement wait time has remained unchanged for patients undergoing a TAVR procedure, suggesting that the increase in capacity has kept pace with the increase in demand. The current wait time of almost 3 months is associated with important morbidity and mortality, suggesting a need for greater capacity and access.                                                 The final paper shows that patients with type 2 diabetes and a history of heart failure are particularly likely to benefit from treatment with the SGLT2 inhibitor canagliflozin. First author, Dr Rådholm, corresponding author Dr Figtree, from Royal North Shore Hospital in Australia, and colleagues, studied more than 10,000 participants with type 2 diabetes and high cardiovascular risk in the CANVAS Program who were randomly assigned to canagliflozin or placebo and followed for a mean of 188 weeks. Participants with a history of heart failure at baseline constituted 14.4% of the study population and were more frequently women, white, and hypertensive, with a history of prior cardiovascular disease. The benefit of canagliflozin on cardiovascular death and hospitalized heart failure was greater in patients with a prior history of heart failure compared to those without heart failure at baseline with a p for interaction of 0.02. The effects of canagliflozin compared with placebo on other cardiovascular outcomes and key safety outcomes were similar in patients with and without heart failure at baseline. Effects were apparent across a broad range of participant subgroups, including those using established treatments for the prevention of heart failure, such as renin-angiotensin-aldosterone system inhibitors, diuretics, and beta-blockers. Thus, patients with type 2 diabetes and a history of heart failure may be particularly likely to benefit from treatment with canagliflozin. The beneficial effects of canagliflozin on heart failure outcomes unlikely to be accrued on top of other therapies for heart failure management.                                                 And that brings us to the end of this week's summaries, now for our feature discussion.                                                 In patients with left main coronary artery disease who are undergoing revascularization, could BNP assessment be that precision medicine tool to aid us in our clinical decision making? Well, I am just so excited to discuss this very topic with the corresponding author for this feature paper, Dr Gregg Stone from Columbia University Medical Center, as well as our associate editor and editorialist for this paper, Dr Torbjørn Omland from University of Oslo.                                                 Gregg, it was a super smart idea to look at circulating BNP and how this may associate with outcomes, as well as therapies in the EXCEL trial. Please tell us what inspired you to do this and please tell us what you found. Dr Gregg Stone:                As everybody knows, BNP has been identified as an important prognostic factor in patients with heart failure and ischemic heart disease. It correlates with both cardiovascular and noncardiovascular mortality. Patients with left main disease are among the highest-risk patients that either interventional cardiologists or cardiac surgeons treat because of the amount of myocardium at risk, they often present in heart failure, and even if they're not in overt heart failure, they can be prone to large severe left ventricular dysfunction. So first we wanted to establish the prognostic utility of BNP in this patient population and then we were interested to see if it might have a role in helping differentiate which patients might have a better prognosis with either PCI or coronary artery bypass graft surgery.                                                 EXCEL is the largest trial to date of left main PCI versus CABG in a randomized format with 1905 enrolled patients. And overall, we found that PCI and CABG had similar rates of deaths, large myocardial infarction, or stroke in 3 years. But of course, there are high risk-patients and low-risk patients buried within those overall aggregate outcomes, and BNP was an important prognostic predictor of overall mortality in the trial. Both cardiovascular and noncardiovascular, but not of any other ischemic end points interestingly. Not myocardial infarction, stent thrombosis, graft occlusion, bleeding, revascularization. But definitely, mortality. Even independent of left ventricular ejection fraction and heart failure status.                                                 Now, when we looked at the outcomes of PCI versus bypass surgery, we actually found a very powerful interaction, such that at relatively lower BNP levels, patients who underwent PCI had a better prognosis and tended to have lower mortality. Where patients with high baseline BNP levels tended to have a better prognosis after surgery. Dr Carolyn Lam:                You know, Torbjørn, I love your editorial where you contextualize these findings so nicely. Could you do that for us now? Dr Torbjørn Omland:      First, I would like to congratulate Gregg and his team with this very interesting and very well-done study, and I think Circulation is very fortunate to be able to publish papers like this. We have known for quite a long time that BNP is a strong prognostic indicator across the spectrum of cardiovascular diseases and it seems to be particularly strongly associated with risk of heart failure events, cardiac arrhythmias, and risk of death. And, as shown in the EXCEL trial, the association with left ventricular ejection fraction is actually quite weak, and also the association with ischemic events. So, these findings fit very well with previous observations. The really novel and intriguing finding of this study is the very strong interaction between procedural BNP levels and the effect of the randomized therapies and, as you alluded to, all the investigators have tried to look at this in other more low-risk populations like in the LIPID trial but actually failed to find any significant interaction. It's really a novel and important finding. Dr Carolyn Lam:                That's true. Does it bring up the question are the natriuretic peptides just a better EF measurement? You mentioned that there was a correlation, what do you think, Gregg? Dr Torbjørn Stone:          Well, you know, there was a weak correlation between BNP and ejection fraction and history of heart failure but the prognostic utility of BNP in this study and its ability to differentiate between the outcomes of PCI versus CABG in patients with low versus high BNP was actually strongly independent of both congestive heart failure history and acute left ventricular ejection fraction. So, I think the BNP is giving a useful independent information. It's a strong reflector of both atrial and ventricular pressures and volume status, but it also reflects myocardial hypoxia, it may be involved in glycolysis and lipid peroxidation, and other mechanisms that we don't fully understand. There may be elements of diastolic dysfunction that we have not measured in this study and other mechanisms related to prognosis in these patients. So, while EXCEL was not set up to truly differentiate and delve deeply into the mechanisms of our observations, statistically these were strong associations that may prove clinically useful. Dr Carolyn Lam:                Right, I thought that was so intriguing as well, just the points that you brought up. First, let's just clarify for the audience that when you say low and high you were using a cutoff of 100. Dr Gregg Stone:                We did use a cutoff of 100 pg per mL as is common, but we also modeled BNP as a continuous measure. And actually the relationships were even stronger when modeled as a log hazard ratio continuous measure, both for mortality and for the primary end point. Dr Carolyn Lam:                Yeah, that's so cool. And Torbjørn, you talked about this in your editorial as well and I thought your point about the distributions of the ejection fraction versus the distribution of natriuretic peptide, that was very revealing, too. Would you like to explain your thoughts there? Dr Torbjørn Omland:      I found it very interesting that all of this is clearly a high-risk operation overall. More than 90% actually had what we regard a normal, or at least not a reduced ejection fraction. Whereas the distribution of BNP values were more widely distributed so that actually about 40% of participants had BNP levels above this ratio of 100 pg per mL. And that probably shows that in this population, BNP provides additional and independent information about the status of the myocardium that is not revealed by angiography or ejection fraction measurements. Dr Carolyn Lam:                That's true, and that's an important point because it added above the SYNTAX score, too, right Gregg? Dr Gregg Stone:                That's right, it was an independent predictor, and in fact the SYNTAX score and the severity of left main coronary disease did not vary, according to BNP levels, that is. High versus low BNP were equally distributed, not related to the anatomic extent and complexity of coronary artery disease. So, BNP is clearly reflecting a different state of the myocardium in a way that we can't measure with any other available test and that makes it quite a useful biomarker. Dr Carolyn Lam:                Exactly, so I think I'd like to wrap up with asking you both, you can already see what the potential clinical implications are, right? Which means that perhaps in a similar type of patient where there's equipoise of the revascularization method and has left main disease, maybe we should be using natriuretic peptides to guide our clinical decision making. What do you think are next steps before this is prime time? Dr Gregg Stone:                Well I can mention that when one makes a decision of the best revascularization modality for patients with extensive multi-vessel or left main coronary artery disease, there are many factors that go into that determination, both clinical, anatomic, is the patient a good candidate for one versus the other revascularization modality, what are the patient's preferences, what's the surgeon's or interventionalist's likelihood of being able to safely get the patient through the procedure and achieve complete revascularization.                                                 The SYNTAX score makes a difference, as does gender and age and kidney disease and COPD and ejection fraction and many other factors. So I think we can now add to that list BNP, although I will say this was a post-hoc study, we only had BNP available in approximately 60% of the patients, and while the outcomes were similar in the patients who we did not versus who we did have BNP, this has to be looked at as hypothesis-generating analysis, and we would love to also see this type of finding replicated in other large datasets. That being said, there are no other large left main or new multi-vessel disease trials that are planned right now to my knowledge, and I think given the breadth of this dataset and its size and scope, I do think that these findings are robust enough to use BNP as one of the clinical factors to consider in revascularization decisions. Dr Torbjørn Omland:      I actually agree with that and I think ideally, we would, of course, like to see external validation in another dataset and even retrospective randomized study comparing conventional versus BNP-guided strategy but that may not be realistically undertaken. So, I think these are clearly the best data we have and as clinicians need to integrate this in our overall evaluation in making this important decision. Dr Carolyn Lam:                Yeah, I mean Gregg, could I ask you, do you apply this clinically already? Dr Gregg Stone:                We have not been before this, although I believe we will now. I believe BNP should be a biomarker that we more routinely measure in patients with ischemic heart disease as well as those with overt congestive heart failure. And again, use as one of the factors of many when making revascularization decisions. And I think it's important to note also that the PCI patients tended to preferentially benefit, in fact with even lower mortality when BNP was lower. Where the surgical patients tended to benefit when BNP was higher. So, it's one factor, not the only factor, but I think it's one additional piece of the puzzle. Dr Carolyn Lam:                Yeah, I have to say too I mean, after reading this, after reading this awesome editorial, it's hard not to think I should be applying this clinically because it's going to be really hard and take a long time to prove this with more prospective data, for example. Although, external validation and other datasets may be better, this is the largest trial already to show this and show it so clearly with a significant interaction. I think that is striking to me.                                                 Torbjørn maybe I've put you on the spot with the last word, does this change your clinical practice? Dr Torbjørn Omland:      I agree with Gregg. This will be one of maybe several other factors but I think it's ready for being taken into account when making this sometimes very difficult decision. Dr Carolyn Lam:                Thank you so much Gregg and Torbjørn for joining me today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.  

Den måtte komme. Debatten med Barstad, Gnatt og Omland om LeBron James' greatness. Poden er spilt inn før game 1 mellom Warriors og Cavs. Gutta snakker om favorittstempelet til Golden State og hvor man plasserer det LeBron har gjort i et historisk perspektiv.

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.                                                 In just a moment, we are going to be discussing the diagnostic conundrum of elevated high sensitivity cardiac troponin levels in a patient with renal disease, but also suspected of acute coronary syndrome. Aha! I bet I caught your attention. A very, very familiar diagnostic dilemma. So stay tuned right after these summaries.                                                 Cardiac allograft vasculopathy is the leading cause of death in patients more than five years post cardiac transplantation. It has been hypothesized that cardiac allograft vasculopathy results from interrupted lymphatic drainage post surgery. Since the donor lymphatic vessels are not inesthimozed to that of the recipient during transplantation, thus the lymphatic system may play a crucial role in the alloimmune response.                                                 Well, these hypothesis are addressed in the first paper in today's journal from first author Dr. Edwards, corresponding author Dr. Wong and colleagues from Kings College, London. These authors use spect CT lymphoscintigraphy in a pre-clinical model. And therefore provided objective quantification of lymphatic flow following transplantation and showed that this correlated to cardiac allograft vasculopathy. They demonstrated that cardiac lymphatic remodeling and lymphatic transport dysfunction post transplant was associated with cardiac allograft vasculopathy and transplant rejection.                                                 They further showed that lymphatic flow was increased during chronic rejection. This in turn may have resulted in enhanced trafficking of antigen presenting cells to the local draining lymph nodes in an augmented alloimmune response. Now although the cause and effect of this phenomenon could not be fully established, these data provided the impetus for the investigation of lymphangiogenesis inhibition as a means to dampen chronic rejection.                                                 The absorb bioresorbable vascular scaffold is known to completely resolve within three years after coronary artery implantation. However, what is the safety and effectiveness of these bioresorbable scaffolds during this critical three year period. First author Dr. Ali, corresponding author Dr. Stone and colleagues from Columbia University Medical Center performed an individual patient level meta analysis of the four randomized absorb trial and demonstrated that compared with metallic everolimus eluting stents, the bioresorbable vascular scaffold had higher rates of target lesion failure and device thrombosis cumulatively to three years and between one and three years. Multi-variable analysis identified the number of treated lesions, current tobacco use and previous cardiac interventions as independent predictors of three year target lesion failure. Whereas diabetes was predictive of three year device thrombosis in bioresorbable vascular scaffold treated patients.                                                 The next paper reported the three year follow up of the FAME 2 trial, which compared PCI guided bi-fractional flow reserve with best medical therapy in patients with stable coronary artery disease to assess clinical outcomes and cost effectiveness. First and corresponding author Dr. Fearon and colleagues from Stanford cardiovascular institute showed that major adverse cardiac events at three years were significantly lower in the PCI group, compared with the medical treatment group. This difference was primarily as a result of a lower rate of urgent revascularization. Mean initial costs were higher in the PCI group, but by three years, were similar between the two groups. The incremental cost effectiveness ratio for PCI compared to medical therapy was more than $17,000 per quality adjusted life year at two years and $1,600 per quality adjusted life year at three years. Thus the authors concluded that percutaneous coronary intervention in patients with stable coronary artery disease and at normal fractional flow reserve may be advantages compared to with medical therapy alone, because it results in improved clinical outcomes and quality of life at no increased cost by the end of three years follow up.                                                 The next study shows for the first time, that pioglitazone may prevent stroke as a single stand-alone outcome. Today's paper by first author Dr. Yaghi, corresponding author Dr. Kernan from Yale School of Medicine and colleagues was a secondary analysis of the iris trial, which showed that pioglitazone reduced the risk for a composite outcome of stroke on myocardial infarction among non-diabetic patients with insulin resistant and a recent stroke or transient ischemic attack. Now, the current planned secondary analysis used updated American Heart Association 2013 consensus criteria for ischemic stroke to examine the effect of pioglitazone on stroke outcomes. The study found that pioglitazone reduced the risk by 25% by five years, with absolute rates of 8% with pioglitazone versus 10.7% with placebo. Pioglitazone reduced the risk for ischemic strokes, but had no effect on the risk of hemorrhagic events. These findings add to the evidence that pioglitazone may be a potent therapy for vascular disease risk reduction and may help inform shared decision making by providers and patients for the use of pioglitazone after ischemic stroke or transient ischemic attack.                                                 Well, that ends it for our summaries. Now for a feature discussion.                                                 The cardiac troponins have really revolutionized cardiology. We use them in of course the diagnosis of myocardial infarction and in fact the recent European Society of Cardiology recommendations say that the rapid zero and one hour triage algorithm for rule in or rule out of non STEMI should use high sensitivity troponins and interestingly irrespective of renal function. Now this latter point has caused some confusion, some questions, since we all know that patients with chronic kidney disease frequently have higher or increased levels of cardiac troponins, especially since we now can detect them with the high sensitivity essays. And this is even in the absence of an acute coronary syndrome.                                                 Well, this week's journal contains two papers that address this topic so well. And I am delighted to have with us the corresponding author of the first paper, Dr. Christian Mueller from University Hospital Basel in Switzerland and the author of the second paper, Dr. Nicholas Mills from University of Edinburgh in Scotland. For the more, we have Dr. Torbjorn Omland, associate editor from University of Oslo in Norway.                                                 Lot's to talk about. Christian, could I start with you? Could you say in your own words the rationale for looking at this vulnerable population and then perhaps describe what you did in your study? Dr. Christian Mueller:     I'm very thankful that Circulation shed a lot of light on the population of patients with renal dysfunction, because both as a clinician and as a researcher, I'm definitely convinced that they merit a lot of our attention for several reasons.                                                 So first, it's important to be aware that the incidents of acute myocardial infarction among patients presenting with acute chest pain is much higher in patients with renal dysfunction, as compared to patients with normal renal function. And second, atypical clinical presentations also are more frequent in patients with renal dysfunction. Then possibly third, the ECG of course also a mandatory tool in our assessment is more often showing unspecific signs that may mimic or obscure the presence of myocardial infarctions and most of them are related to left ventricular hypertrophy. And in addition, patients with renal dysfunction are more prone to adverse events, both related to cardiovascular medication. For example, anticoagulation as well as our cardiovascular procedures, including PCI. Now again, as both papers have a strong focus on troponin, also cardiac troponin is a bit more difficult to interpret in patients with renal dysfunction related to exactly as you mentioned chronic elevations of cardiac troponin, TNI related to chronic cardiovascular disease.                                                 And I think that's so important to stress, any troponin signal in a patient with renal dysfunction is real and should not be incorrectly attributed to just a problem of impaired secretion by the kidneys. Dr. Carolyn Lam:               So definitely an even greater need to diagnose myocardial infarction accurately in this very high risk population. So tell us what you did. Dr. Christian Mueller:     We assessed this challenging sub group within the APACE study. So APACE is a large international prospective diagnostic study that is run in five countries with 12 centers. And we actually enroll consecutive patients presenting with suspected myocardial infarction. And then all patients get a very detailed workup and then adjudicated final diagnosis. And the adjudicated file diagnosis is done by two independent cardiologists and is based on two enormous extensive sets of data. The clinical data set that has been obtained at the local site and of course includes cardiac imaging and standard troponin testing, ECG data.                                                 In the second set of data that includes the study specific data sets, including serial measurements with high sensitivity carry troponin essay and a lot of details characterization of patients and patient follow up. So this is the reference standard against which the one hour algorithm the European Society of Cardiology evaluated. And the one hour algorithm has been derived and previously validated in overall population. Mainly patients with normal renal function. And so we tried to evaluate the performance of this predefined algorithm specifically in patients with renal dysfunctions.                                                 So among a bit more than 3,000 patients, the prevalence of patients with renal dysfunction was 15%. So we had about 500 patients with renal dysfunction. And the interesting finding from our work is that first the prevalence of N-STEMI was nearly threefold in patients with renal dysfunction as compared to patients with normal renal function. And, fortunately the rule out part of the algorithm regarding sensitivity still works very well. It is, however, the efficacy of rule out that is lower in patients with renal dysfunction, simply because fewer patients really have very low troponin concentration and are therefore ineligible for rule out.                                                 However, as a clinician, the main concern with troponin and renal dysfunction is the rule in part, and specificity. And as you would think, specificity of the one hour algorithm was in fact significantly lower in patients with renal dysfunction. It was still appropriate for therapeutic consequences, but it was lower as compared to patients with normal renal function, so the specificity was 89% in patients with renal dysfunction, as compared to 96.5% in normal renal function.                                                 So the overall efficacy of the algorithm was lower in patients with renal dysfunction, however then when trying to create and derive optimized cut off levels, so all cut off levels optimized for use in renal dysfunction, we didn't really find alternative cut offs that would do a much better job than the official cut off levels recommended in the guidelines. So our conclusion is that in patients with renal dysfunction, the safety of the one hour algorithm still is very high, however the specificity of rule in and overall efficacy are decreased. Dr. Carolyn Lam:               Right. That's beautifully summarized. And also that different cut offs didn't really help to increase the efficacy of this algorithm. And just to clarify to our listeners, I believe you defined renal dysfunction as an estimated GFR of less than 60, which is so beautiful because it's perfectly consistent with the second paper.                                                 Nick, could you please tell us about your study and your take home messages as well. Dr. Nicholas Mills:            So high stakes is our clinical trial that we're conducting across hospitals in Scotland to evaluate the best way to use high levels of cardiac troponin in clinical practice. One of the areas of uncertainty is whether these assets really add any additional value for patients with chronic kidney disease, where troponin concentrations tend to be higher. And the premise of a high sensitive test is that we can measure lower concentrations and improve the sensitivity. But is this just going to create uncertainty for clinicians?                                                 So we evaluated 5,000 consecutive patients for performance of high sensitivity cardiac to put in testing. And those with and without renal impairment. And based upon what Christian, we identified that patients with renal impairment are less likely to have very low concentrations, but that you can rule out myocardial infarction safely in patients with renal impairment. And similarly that those with renal impairment are more likely to have an abnormal troponin concentration at presentation. Around about 40% of all patients have troponins above the upper reference limit. And whilst the specificity for myocardial infarction is lower, type one myocardial infarction or myocardial infarction due to plaque rupture or cardiac thrombosis remains the most common diagnosis in this group.                                                 Finally we looked at one year outcomes. And this is really critical. Because we found that patients with renal impairment were two to threefold more likely to die from cardiovascular disease one year following their presentation than those without renal impairment. And I think that my general experience during these tests in clinical practice is that troponin elevations in patients with kidney disease are often ignored and there's a concern about what they mean, and therefore these patients don't get access to the fantastic treatments we have for coronary heart disease. So our take home message is that high sets of troponin testing in patients with renal disease does have value, it's useful for identifying low risk patients although there are fewer of them, and it performs well as a diagnostic test, highlighting in particular a group of patients that really have poor clinical outcomes.                                                 As a cardiological community, we need to do better. Dr. Carolyn Lam:               What I really love about both or your papers is the consistency in the messages. Torbjorn, I want to bring you in on this. You managed both papers. Such a lovely pair of papers that we're so proud to be publishing and you had also invited an editorial by Dr. deFilippi and Seliger. Would you like to comment on your perspective and perhaps the clinical take home message to our audience? Dr. Torbjørn Omland:     Yes, I think this has been pointed very well out by both Christian and Nick. And I think it's worth recapitulating that renal dysfunction is a major problem that clinicians often try to explain by just lack of renal filtration. But that the closest probably are increased production and underlying cardiac disease. So in the editorial Dr. deFilippi Filippi and Dr. Seliger points also out in these things. Moreover they try to look forward and have made comments to recent studies that showed that in patients with renal dysfunction have different troponin fragments than patients with acute myocardial infarctions. Dr. Carolyn Lam:               I find that so fascinating. And it really, really relates to the field of heart failure and what we are also talking and thinking about with natriuretic peptides and their different fragments and the possible different meanings. And how different essays maybe non specific for different fragments.                                                 Christian, you think a lot about these things. I'm curious, what are your thoughts on this and areas of future work that are very urgent? Dr. Christian Mueller:     I think Torbjorn very nicely addressed this. So the current high sensitivity essays for T and I that we use in clinical practice, they are designed kind of to detect everything in blood that looks like troponin, either T or I, including various fragments. And I think it's a fantastic new avenue of research, trying to find out that the biochemical signatures can be further differentiated and exactly that perhaps different troponin fragments or tricordinate products more prominent in patients having ischemic injuries like treat myocardial infarction, as compared to for example other modes of injuries. So I think that's very nice hypothesis and some early data. But at least from my perspectives and to the best of my knowledge until now, the diagnostic algorithms that we have other ways to approach this in clinical practice. And so it's the higher the blood concentration in patients with acute chest pain, the more likely it's acute myocardial infarction. It's not any chronic disease and again the higher the change from presentation to one hour or two hours, the more likely it's acute as a dynamic disorder resulting in an acute increase in cardiac troponin, as compared to the chronic release patterns typically seen in patients with renal dysfunction. Dr. Carolyn Lam:               Yeah. That's just so fascinating. Nick, we sadly are running out of time, but I do want to give you the last word. The clinical take home message, once again. What do you think listeners should take home that may change their practice, after listening to this podcast? Dr. Nicholas Mills:            I think the key message for clinicians, is that in a patient with suspected acute coronary syndrome and has renal impairment and elevated troponin concentration, serial testing is mandatory to differentiate between those that have chronic myocardial injury due to subclinical heart disease and those that are having acute myocardial injury as a consequence of a presumed acute coronary syndrome. Field testing is critical to inform which treatment path and what investigations we recommend for our patients. Dr. Carolyn Lam:               Wonderful. And to take any elevations seriously, because this is a high risk population.                                                 Well, audience you heard it right here on Circulation On The Run. I'm sure you've enjoyed this. I certainly have. Don't forget to tune in again next week.  

Episode 40, hail the Reignman, av Time Out! Fred Gnatt, Mags Barstad og Stig Omland tenker høyt om Melo til OKC. Hvem har gutta som de 3 beste duoene i dagens NBA? Og hvilket lag har Gnatt og Barstad på 3. i East, som Omland har på 7. plass?? Enjoy!

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. Today we will be discussing the pooled analysis results of the 10 ODYSSEY Trials with important implications for the reduction of lipids in major cardiovascular events. But first, here's your summary of this week's journal. The first paper provides experimental data on vascular disease that brings into focus the critical roles of transcription factors such as GATA2 in the maintenance of endothelial cell function, as well as the role of selected microRNAs as a novel player of vascular regulation. In this study by first author Dr. Hartman, corresponding author Dr. Thum from Hanover Medical School, and colleagues, authors used GATA2 gain and loss of function experiments in human umbilical vein endothelial cells to identify a key role of GATA2 as a master regulator of multiple endothelial functions, and this via microRNA-dependent mechanisms. Global microRNA screening identified several GATA2-regulated microRNAs, including miR-126 and miR-221. GATA2 deficiency led to vascular abnormalities, whereas supplementation with miR-126 normalized vascular function. In a mouse model of carotid injury, GATA2 was reduced and systemic supplementation of miR-126-coupled nanoparticles enhanced miR-126 availability in the carotid artery and improved reendothelialization of injured carotid arteries in vivo. In summary, GATA2-mediated regulation of miR-126 and miR-221 has an important impact on endothelial biology. Thus, modulation of GATA2 and its targets miR-126 and miR-221 represents a promising therapeutic strategy for the treatment of vascular diseases. The next study is the first to show that current smokers from the general population have lower levels of circulating cardiac troponin I, a seemingly paradoxical observation given the known detrimental cardiovascular impact of cigarette smoking. First author Dr. Lyngbakken, corresponding author Dr. Omland, and colleagues from the University of Oslo used data from the large population-based HUNT study, in which cardiac troponin I was measured in 3,824 never smokers, 2,341 former smokers, and 2,550 current smokers. Current smokers had significantly lower levels of cardiac troponin I than never smokers and former smokers, an association that remains significant even after adjustment for potential confounders. The authors also found an association between increasing concentrations of troponin I and clinical endpoints, namely acute myocardial infarction, heart failure, and cardiovascular death in the total cohort. However, this association was attenuated in current smokers and was significantly weaker than in never or former smokers with a p for interaction of 0.003. The prognostic accuracy of troponin I as assessed by C-statistics was lower in current smokers than in never smokers. Troponin I provided no incremental prognostic information to the Framingham Cardiovascular Disease risk score in the current smokers. Together, these results suggest that mechanistic pathways other than those involving subclinical myocardial injury may be responsible for the cardiovascular risk associated with current smoking. Future studies are needed to determine whether a lower cardiac troponin I threshold should be considered for exclusion of myocardial infarction in smokers or whether prognostic tools other than measurement of cardiac troponins should be utilized when evaluating risk of future events in current smokers. The next study contributes to our understanding of cardiomyocyte signaling in response to ischemic injury. In the study by first author Dr. [Wool 00:05:04], corresponding author Dr. [Ju 00:05:04] from Tongji University School of Medicine in Shanghai, and colleagues, authors sought to understand the role of low-density lipoprotein receptor-related proteins 5 and 6 as well as beta-catenin signaling in the heart. They did this using conditional cardiomyocyte-specific knockout mice who had surgically induced myocardial infarction. They found that deletion of lipoprotein receptor-related proteins 5 and 6 promoted cardiac ischemic insults. Conversely, deficiency of beta-catenin, a downstream target, was beneficial in ischemic injury. Interestingly, although both insulin-like growth factor-binding protein 4 and Dickkopf-related protein 1 are secreted beta-catenin pathway inhibitors, the former protected the ischemic heart by inhibiting beta-catenin, whereas the latter enhanced the injury response mainly through inducing lipoprotein-related protein 5 and 6 endocytosis and degradation. These findings really add to our understanding of the beta-catenin signaling pathway in ischemic injury and suggests that new therapeutic strategies in ischemic heart disease may involve fine-tuning these signaling pathways. The next paper from the International Consortium of Vascular Registries is the first study allowing an assessment of variations in repair of abdominal aortic aneurysms in 11 countries over 3 continents represented by the Society of Vascular Surgery and European Society for Vascular Surgery. Dr. Beck from University of Alabama-Birmingham School of Medicine, and colleagues, looked at registry data for open and endovascular abdominal aortic aneurysm repair during 2010 to 2013, collected from 11 countries. These were Australia, Denmark, Hungary, Iceland, New Zealand, Norway, Sweden, Finland, Switzerland, Germany, and the United States. Among more than 51,000 patients, utilization of endovascular aortic repair for intact aneurysms varied from 28% in Hungary to 79% in the United States, and for ruptured aneurysms from 5% in Denmark to 52% in the United States. In addition to the between-country variations, significant variations were present between centers within each country in terms of endovascular aortic repair use and rate of small aneurysm repair. Countries that more frequently treated small aneurysms tended to use the endovascular approach more frequently. Octogenarians made up 23% of all patients, with a range of 12% in Hungary to 29% in Australia. In countries with a fee for service reimbursement systems, such as Australia, Germany, Switzerland, and the United States, the proportion of small aneurysms and octogenarians undergoing intact aneurysm repair was higher compared to countries with a population-based reimbursement model. In general, center-level variation within countries in the management of aneurysms was as important as variation between counties. Hence, this study shows that despite homogeneous guidelines from professional societies, there is significant variation in the management of abdominal aortic aneurysms, most notably for intact aneurysm diameter at repair, utilization of endovascular approaches, and the treatment of elderly patients. These findings suggest that there is an opportunity for further international harmonization of treatment algorithms for abdominal aortic aneurysms. This is discussed in an accompanying editorial entitled, Vascular Surgeons Leading the Way in Global Quality Improvement, by Dr. Fairman. The final paper from Dr. Gibson at Beth Israel Deaconess Medical Center and Harvard Medical School and colleagues, presents the results of the apoAI event reducing in ischemic syndromes I, or AEGIS-I, trial, which was a multicenter, randomized, doubleblind, placebo-controlled dose-ranging phase 2b trial of CSL112, which is an infusible, plasma-derived apoAI that has been studied in normal subjects and those with stable coronary artery disease, but now studied in the current study in patients with acute myocardial infarction. The trial showed that among patients with acute myocardial infarction, four weekly infusions of a reconstituted, infusible, human apoAI, CSL112, was associated with a dose-dependent elevation of circulating apoAI and cholesterol efflux capacity without adverse hepatic or renal outcomes. The potential benefit of CSL112 to reduce major adverse cardiovascular events will need to be assessed in an adequately powered phase 3 trial. Now for our future discussion. Today I am delighted to have with us Dr. Kausik Ray from Imperial College London, who's the first and corresponding author of a new paper regarding the pooled analysis of the 10 ODYSSEY Trials. To discuss it with us is Dr. Carol Watson, associate editor from UCLA. Kausik, just let me start by congratulating you on this paper. I believe this is the first data that allows us to look under the 50 mg/dL mark of LDL and really ask if the LDL MACE relationship extends below this level. Dr. Kausik Ray: Yes, the reason for looking at this is that the IMPROVE-IT trial really looked at people down to an average LDL cholesterol of about 54, and with the new PCSK9 inhibitors, which instead of giving you a 20% further reduction LDL, they give you the opportunity for a further 50 to 60% reduction. We actually get the chance to get people down to levels like 25 mg/dL, and the question is, does the benefit continue at that level? We did a pooled analysis of 10 of the ODYSSEY Trials, really in some ways to try and help predict what you might see in ODYSSEY outcomes, what you might see in the [Fuliay 00:12:00] trial, and to also manage expectations as well, because there's probably been a lot of hype around the two New England Journal papers about 50, 60% reductions of all potential reductions based on small numbers of events. So the question is, if you reduce LDL by 39 mg/dL, how might that reduce your risk, and is the relationship continuous? So those were the aims. Dr. Carolyn Lam: That's great, and maybe could you give us an idea of the number of patients you are looking at and the number of events? Dr. Kausik Ray: Yeah. In the 10 pool studies, we had just under 5,000 individuals, and we had just about 6,700 person years' worth of followup. In total, we had 104 first MACE events. To put this into context, it's about one third of the number of events that the first [framing 00:12:53] of analysis had. It's an observation analysis rather than randomized trial data, so you got to bear that in mind with the usual caveats that go with observational data. But the same endpoints that were adjudicated, this is [inaudible 00:13:10] heart disease death, non-fatal MI, ischemic stroke, and unstable angina requiring hospitalization. This is the same endpoint that is in the ODYSSEY Outcomes Trial, so it's interesting in that regard. Dr. Carolyn Lam: Yeah, it sure is. So what's the bottom line? What did you find? Dr. Kausik Ray: What we found was that there was a continuous relationship all the way down to LDL cholesterol levels of about 25 mg/dL, that every 39 mg/dL lower on treatment LDL, your risk went down by about 24%. If you looked at [apo-like 00:13:48] approaching be on non-HDL cholesterol, again, you found the same continuous relationship with a similar point estimate for a similar standardized difference in LDL cholesterol. We also looked at many of the guidelines, talk about percentage reduction. We actually looked at percentage reductions. If you start with a baseline LDL of X and you achieve a 50% further reduction in LDL, how much further benefit does that give you? A 50% further reduction gave you a 29% further lower risk of MACE. So we didn't find any threshold or limit all the way down to LDLs of about 25. Dr. Carolyn Lam: That's really a key, novel finding that you contributed, so congratulations once again. I suppose the question will always be, you're talking about relative risk reductions here. At such low levels, can you give us an idea of the absolute risk reductions? Dr. Kausik Ray: Yes. You've got to remember that the relative risk reductions are what you can apply to population differences. If you pick a high-risk patient population, you would expect to see a much bigger absolute risk reduction than maybe this study or another study. Similarly, if you pick a low-risk group, you are going to see a much smaller absolute benefit. I always try to advise a little bit of caution that if you basically look at the range ... If you start with let's say an LDL of 150 and you go down to let's say an LDL of 25, you are talking about a 1.25% absolute risk reduction. Remember, these patients are possibly going to be a slightly lower risk than the ones that are recruited into the ODYSSEY Outcomes and into the [Fuliay 00:15:46] trial, for example. Dr. Carolyn Lam: I think you mentioned what I was going to just ask you about. This is observational. You had 104 events, and I suppose another limitation might be that your followup was two years at max, if I'm not wrong? What do you say about that, and are there plans for future analyses? Dr. Kausik Ray: Within the context of these studies, I think that the whole of this data will eventually become dwarfed by what we see with the big CDOTs, because you've got 18, 27,000 people, 3 years' worth of exposure and followups, so you are going to have many, many more events. That is a limitation, but I think what is interesting is that we know that the baseline LDL cholesterol level is around about 90 mg/dL. We don't actually know what the actual baseline ... because the baseline [characters 00:16:43] haven't been published for ODYSSEY Outcomes, but the [Fuliays 00:16:46] around about 89. What it tells you is what the point estimate is likely to be. It's likely to be in the 24 to 32% ballpark because that's what your baseline LDL is and that's what we'd predict in the regression lines that we observed here. I think that we're not going to get many more events in these studies because largely the randomized period of followup is now over. Many of these people are now into open labels, extensions for safety, so we won't get many more events from this. In terms of, I think, the way people should maybe look at this is possibly as a taster for what's to come in the next 18 months or so. I think for the time being it answers two questions. Is lower likely to be better? And it is. I think the other question it tells is how might you get people down to LDLs below 50? One of the important things was that if you were just on statins, in this population, if you were recruited on the basis of a high baseline LDL, you got no additional people down to LDLs below 50. You got under 10% with add-on [inaudible 00:18:05], but you got around about 50% when you used the PCSK9 inhibitor as an add-on to existing therapy. It tells you about how to get to such low levels as well. I think that's the other key thing that it actually gives you. We did an analysis of safety [inaudible 00:18:23], and I think that's really important. Once you see the efficacy, or if you see the MACE events continue to go down ... If you looked at treatment-emergent adverse events ... and I completely take the fact that it's every side effect reported altogether, which may or may not be linked to LDL levels specifically, but when we did that, the relationship actually was just a horizontal line, so there was no relationship with percentage reduction or on treatment LDL, so it gave us a nice idea of both safety and efficacy that we might experience in the big outcome studies. Dr. Carolyn Lam: All right. Obviously the big outcome studies are going to be game changers, and I'd really love to invite [Carol Scotts 00:19:09] here, because there's a whole lot of other things that need to be considered if this becomes the case, isn't it? Carol, I really appreciated that you invited an editorial, and the editorial is by Neil Stone who entitles it, Looking Beyond Statins: Will the Dollars Make Cents? Please tell us about the discussions about this paper that occurred. Dr. Carol Lam: I would again like to congratulate Dr. Ray on a fantastic paper, and I would like to reiterate exactly what he said. I think it really does give us some comfort about this class of medication and its relative safety. I think that's very important, because I can't tell you how many patients I get and how many referring physicians I get who worry when their patients come back with LDLs of 20 or below. I think that gave us some comfort, and I do also think it was very important to show that this would fall along the same regression line that statins perhaps would fall. As with all the caveats that Dr. Ray said, I agree with all of them, but I do say this is a tasty little taster, and I appreciate and congratulate you for publishing this. The editorial by Dr. Neil Stone was quite interesting. As you said, he subtitled it, Will the Dollars Make Cents? C E N T S or S E N S E, sort of a play on words there. Will the relative benefits that we can achieve with this class of medications make sense for the cost of these drugs? That's obviously a very separate issue from what was discussed in the manuscript, but it's something to think about. We understand that there are additional patients that will be helped if they can get their LDL down, and we hope that that will translate into the outcomes. Again, just as Dr. Ray mentioned, we will have to wait for the cardiovascular outcomes trials to be completed. When they are, if they do show the benefits that we hope, will their price point make them accessible to enough patients for this to be a widely applied, utilized therapy? Or will they not? That's part of what was discussed in Dr. Stone's editorial. Dr. Kausik Ray: When we were writing the manuscript and stuff like that, and we were doing this and everybody's like, "Oh, wow, look at the graphs." I said, "Look, we need to balance all of these bits and reassure ... We've got an opportunity." So I suggested them giving those additional analyses, and you saw how big the online supplement was. There was a ton of work that we put into this, and to format it into a concise ... I really want to just thank the editorial board for giving us the chance and actually being able to help us and work with us on this, because it's really important. I hope people look at all of those things because it will help people also that question the LDL. They all talk about the hypothesis and the safety of really low LDLs, and people come off statins as a result. I think this will help. Dr. Carolyn Lam: You're listening to Circulation on the Run. Thank you so much for being with us, and don't forget to tune in next week.