Podcasts about lvf

Conegliano è campione d'Italia. Commentiamo l'ennesimo successo in tre gare delle venete su Milano, prima di fare il nostro solito giro per i vari campionati mondiali e il commento al bracket delle opposte....P1 è un podcast di cronaca e analisi delle ultime novità nel mondo della pallavolo. Le nazionali da maggio a ottobre, campionati italiani e coppe europee per la stagione autunno-inverno. Un occhio al femminile e uno al maschile. I nostri social:Instagram:  https://www.instagram.com/p1_podcastdivolley/ Intro: Happy AI Technology by Abydos_Music via Pixabay (per W) Mysterious Sci Fi by Brotheration_Records via Pixabay (per M) Sottofondo: Music track: Forest by Damtaro Source: https://freetouse.com/music Free To Use Music for Video

Durant la Seconde Guerre mondiale, plusieurs milliers de Français firent le choix de s'engager non pas dans la Résistance… mais dans les rangs de l'armée allemande. Parmi eux, environ 2 500 furent enrôlés dans la division Charlemagne, une unité de la Waffen-SS, l'aile militaire du parti nazi. Une décision choquante pour la mémoire collective, mais qui répond à des logiques idéologiques, politiques et personnelles complexes.Le contexte du recrutementDès 1941, après l'invasion de l'URSS par l'Allemagne nazie, le régime de Vichy et les collaborateurs parisiens intensifient leur propagande contre le "bolchevisme", présenté comme l'ennemi absolu. Dans ce climat, de nombreux Français issus de l'extrême droite, des milieux fascistes ou ultra-catholiques voient dans l'Armée allemande un rempart contre le communisme.C'est dans ce cadre que naît d'abord la Légion des Volontaires Français contre le Bolchevisme (LVF), en 1941, qui combat sous l'uniforme allemand sur le front de l'Est. Mais en 1943, la SS décide de créer une unité spécifique pour les volontaires étrangers : la division SS Charlemagne, formée en 1944 à partir des survivants de la LVF, de la Milice, et d'anciens membres de la Gestapo française.Pourquoi s'engager dans la Waffen-SS ?Les motivations sont multiples :Idéologiques : Certains étaient sincèrement acquis à l'idéologie nazie, admirateurs d'Hitler, antisémites convaincus ou anticommunistes radicaux.Politiques : D'autres voyaient l'adhésion à la Waffen-SS comme un moyen d'accélérer la collaboration entre la France et l'Allemagne, rêvant d'une Europe nouvelle, dirigée par l'Allemagne nazie.Opportunistes : Pour certains jeunes en rupture, engagés tardivement, c'était une voie pour échapper à la misère, à des poursuites judiciaires ou au Service du Travail Obligatoire (STO).Par fanatisme ou fatalisme : Surtout après la Libération, certains collaborateurs français rejoignent la Charlemagne comme dernier refuge, préférant fuir vers l'Est plutôt que de tomber aux mains des Alliés.La division Charlemagne sur le frontLa division est engagée en Poméranie début 1945, où elle subit des pertes terribles face à l'Armée rouge. Une centaine de survivants participe ensuite à la défense de Berlin en avril 1945, dans les tout derniers jours du régime nazi. Ces SS français figurent parmi les derniers défenseurs du bunker d'Hitler. Certains, comme Henri Joseph Fenet, se distinguent par leur fanatisme, recevant même des décorations nazies.Une mémoire taboueAprès la guerre, les survivants furent jugés pour trahison, certains exécutés, d'autres emprisonnés. Le sujet resta longtemps tabou en France, tant il heurtait l'image d'un pays tout entier résistant. Pourtant, l'histoire de la division Charlemagne rappelle que la collaboration militaire avec le nazisme a aussi été une réalité française — marginale, mais bien réelle. Hébergé par Acast. Visitez acast.com/privacy pour plus d'informations.

Continuano le semifinali e finiscono a metà: Trento passa per 3 a 0, anche se Piacenza forse meritava una serie più lunga, mentre Civitanova, sotto 2 gare a 0, la riportà in parità. Si decide tutto giovedì.In coda, continua il nostro giro nei principali campionati europei e mondiali, con aggiornamento sugli sviluppi nelle corse scudetto....P1 è un podcast di cronaca e analisi delle ultime novità nel mondo della pallavolo. Le nazionali da maggio a ottobre, campionati italiani e coppe europee per la stagione autunno-inverno. Un occhio al femminile e uno al maschile. I nostri social:Instagram:  https://www.instagram.com/p1_podcastdivolley/ https://www.instagram.com/una_tifosa_del_volley/ Intro:Mysterious Sci Fi by Brotheration_Records via Pixabay Sottofondo: Music track: Forest by DamtaroSource: https://freetouse.com/musicFree To Use Music for Video

Come siamo giunti all'ennesima finale Milano-Conegliano, con biasimi a Scandicci e lodi a Novara e alla grande stagione sua e della sua opposta. Stagione culminata con la vittoria della coppa CEV, di cui parliamo, prima di fare un giro nei principali campionati mondiali a vedere come stanno andando coppe e playoffs scudetto....P1 è un podcast di cronaca e analisi delle ultime novità nel mondo della pallavolo. Le nazionali da maggio a ottobre, campionati italiani e coppe europee per la stagione autunno-inverno. Un occhio al femminile e uno al maschile. I nostri social: Instagram:https://www.instagram.com/p1_podcastdivolley/Intro: Happy AI Technology by Abydos_Music via PixabaySottofondo: Music track: Forest by DamtaroSource: https://freetouse.com/musicFree To Use Music for Video

Quattochiacchiere con Giovanni Maria Gargiulo, centrale della Lube: dagli esordi alla Materdomini, sino all'anno attuale con la vittoria della Coppa Italia (con retroscena sulla serata prima della finale). Nel mezzo le esperienze a Vibo e Taranto, hobby e dietro le quinte, per una panoramica a 360° su Giovanni Gargiulo....P1 è un podcast di cronaca e analisi delle ultime novità nel mondo della pallavolo. Le nazionali da maggio a ottobre, campionati italiani e coppe europee per la stagione autunno-inverno. Un occhio al femminile e uno al maschile. I nostri social:Instagram:https://www.instagram.com/p1_podcastdivolley/https://www.instagram.com/una_tifosa_del_volley/Intro:Mysterious Sci Fi by Brotheration_Records via Pixabay Sottofondo:Music track: Forest by DamtaroSource: https://freetouse.com/musicFree To Use Music for Video

Le semifinale scudetto, a gara 1, con le vittorie di Perugia su Civitanova e di Trento su Piacenza, caratterizzate dalle grandi prestazioni di tre palleggiatori su quattro. Questo prima di due parole sulla finale di CEV Cup, e un rapido giro per vedere la situazione negli altri campionati....P1 è un podcast di cronaca e analisi delle ultime novità nel mondo della pallavolo. Le nazionali da maggio a ottobre, campionati italiani e coppe europee per la stagione autunno-inverno. Un occhio al femminile e uno al maschile. I nostri social:Instagram:  https://www.instagram.com/p1_podcastdivolley/ https://www.instagram.com/una_tifosa_del_volley/ Intro:Mysterious Sci Fi by Brotheration_Records via PixabaySottofondo: Music track: Forest by DamtaroSource: https://freetouse.com/musicFree To Use Music for Video 

Le epiche ultime due settimane di Novara, fra quarti di finale scudetto, finale di Coppa CEV e semifinale -sempre scudetto- contro Conegliano. Per concludere l'altra semi, con Milano che domina gara 1 e la spunta al tie break al ritorno, portando la serie sul 2-0....P1 è un podcast di cronaca e analisi delle ultime novità nel mondo della pallavolo. Le nazionali da maggio a ottobre, campionati italiani e coppe europee per la stagione autunno-inverno. Un occhio al femminile e uno al maschile. I nostri social:Instagram:  https://www.instagram.com/p1_podcastdivolley/Intro: Happy AI Technology by Abydos_Music via PixabaySottofondo: Music track: Forest by DamtaroSource: https://freetouse.com/musicFree To Use Music for Video

L'émission 28 minutes du 31/03/2025 Il retrace l'itinéraire criminel de son père, engagé avec les nazis au sein de la LVFLe 22 juin 1941, Adolf Hitler déclenche le plan Barbarossa. Objectif : conquérir l'Union soviétique et en finir avec le communisme. Aux côtés du régime nazi, la Légion des volontaires français (LVF), une organisation créée par des partis collaborationnistes, prend part à cette conquête. D'abord affectée sur le front, elle sera ensuite intégrée à la Waffen-SS pour participer à ce que l'on appelle la “Shoah par balles”, un massacre de masse ayant conduit à la mort de près d'un million et demi de juifs d'Ukraine. Parmi ces collaborationnistes figure Alfred Douroux, dit Freddy, anticommuniste viscéral et antisémite. Il ne s'engage dans la LVF qu'en mars 1943, au moment où la défaite de l'Allemagne nazie devient probable. À la fin de la guerre, il parvient à rentrer en France et à fonder une famille. Il aura trois fils parmi lesquels Philippe Douroux, né en février 1955.  Cet ancien journaliste à "Libération" publie “Un père ordinaire” (aux éditions Flammarion), un livre dans lequel il revient sur l'itinéraire de ces volontaires de la LVF nourris par la haine et le goût de l'argent, et qui ont bénéficié d'une incroyable immunité après la guerre.Face aux droits de douane de Trump, faut-il répliquer œil pour œil dent pour dent ?Donald Trump a fait des droits de douane sur les produits importés son principal cheval de bataille économique. Le Canada, le Mexique, la Chine, l'Union européenne, ses principaux partenaires commerciaux, sont les premiers concernés par cette nouvelle politique de taxation. Depuis son entrée en fonction, de nombreuses mesures ont été mises en place comme l'instauration de taxes douanières, toujours en négociation, sur les produits mexicains et canadiens importés aux États-Unis, la taxation de produits européens et une taxe supplémentaire sur l'acier et l'aluminium européens. La dernière mesure en date est l'imposition de droits de douane sur toutes les voitures qui ne sont pas fabriquées aux États-Unis, mais Donald Trump ne s'arrête pas là. Il doit annoncer mercredi 2 avril la mise en place de droits de douane dits “réciproques” visant le monde entier, dans une journée baptisée “Liberation Day”. Face à cette offensive américaine, les consommateurs risquent d'être les grands perdants puisque le coût des produits sera plus élevé.Enfin, Xavier Mauduit nous raconte une histoire océanique avant le sommet "SOS Océans", qui se tiendra en France, pour la protection des océans. Marie Bonnisseau revient sur l'histoire du nageur congolais Freddy Mayala, premier athlète à obtenir le statut de réfugié des Jeux olympiques 2024.  28 minutes est le magazine d'actualité d'ARTE, présenté par Élisabeth Quin du lundi au jeudi à 20h05. Renaud Dély est aux commandes de l'émission le vendredi et le samedi. Ce podcast est coproduit par KM et ARTE Radio. Enregistrement 31 mars 2025 Présentation Élisabeth Quin Production KM, ARTE Radio

I quarti di finale del campionato più bello del mondo e il finale delle coppe Europee, con 2 finaliste su 2 in Challenge Cup, 1 su in Coppa CEV e 3 su 4 in Champions League....P1 è un podcast di cronaca e analisi delle ultime novità nel mondo della pallavolo. Le nazionali da maggio a ottobre, campionati italiani e coppe europee per la stagione autunno-inverno. Un occhio al femminile e uno al maschile. I nostri social: Instagram: https://www.instagram.com/p1_podcastdivolley?igsh=MXM0bG9zbXltOTJ6YQ== Intro: Happy AI Technology by Abydos_Music via PixabaySottofondo: Music track: Forest by DamtaroSource: https://freetouse.com/musicFree To Use Music for Video

La regular season è finita, evviva la regular season! Verdetti, griglia playoffs e la sbirciatina solita alle italiane in Europa....P1 è un podcast di cronaca e analisi delle ultime novità nel mondo della pallavolo. Le nazionali da maggio a ottobre, campionati italiani e coppe europee per la stagione autunno-inverno. Un occhio al femminile e uno al maschile. I nostri social:Instagram: https://www.instagram.com/p1_podcastdivolley?igsh=MXM0bG9zbXltOTJ6YQ== Intro: Happy AI Technology by Abydos_Music via PixabaySottofondo: Music track: Forest by DamtaroSource: https://freetouse.com/musicFree To Use Music for Video

Ever been that only Black or Latino or Asian person in the room? And you had to advocate for your community's interests too? This is something Sindy Benavides faced a lot throughout her career that led her to work for civil rights organizations working on behalf of the larger Latino community. As President of the Latino Victory Fund (LVF), Sindy's day to day is focused on building political power for Latinos at the local, state and federal level and advocating for issues important to this constituency as well. As a long time colleague and friend in the work, we talk about everything including: her and life and career and why she thought it important to go to an HBCU for college (and how that informs her work today), how she got her start in politics, the importance of trusting your gut and speaking your truth (even if does make you anxious as hell), we also get to what happened with the Latino Vote in the 2024 election and what she and LVF are planning for the road ahead.If you enjoyed the show and you want to join our community of other women of color who are embracing their voice head over to https://embracingyourvoicepod.com/Connect with Atima on:InstagramTwitterLinkedin

Martin O'Hagan was a former IRA prisoner who eventually rejected violence and became an investigative reporter with the Sunday World. He was murdered by the LVF in Lurgan on 28th of September 2001. No-one has ever been convicted of the killing. The National Union of Journalists wants an independent inquiry into the killing and the subsequent investigation into it. Ciarán Dunbar is by joined by Anton McCabe, Seamus Dooley, and by Jim McDowell, Martin O'Hagan's editor at the Sunday World. Hosted on Acast. See acast.com/privacy for more information.

I dagens avsnitt berättar jag lite om min gemenskap för kvinnor, för dig som kanske är ny här, välkommen hit. En gemenskap där du kan bli mer av den du är. Där du får växa, lära och utvecklas. Där du kan leva ditt liv i sanning med den du är och ta din plats fullt ut. Jag berättar också om ett av mina absoluta favoritämnen, nämligen att närvaro är kärlek. När vi är helt närvarande och verkligen ser, hör och bekräftar en annan person skapas en positiv spiral i mötet. Den vi möter känner sig sedd, hörd och bekräftad, vilket vi människor behöver och det gör att vi öppnar upp och känner oss mer trygga och vågar vara mer i vårt sanna och autentiska jag. Det leder till att relationen utvecklas och fördjupas. När vi är mer intresserade av den andre personen än av oss själva. När vi kliver ur vårt ego och in i närvaron i nuet. När vi kan släppa våra egna tankar och åsikter en stund, vi behöver inte tänka ut något smart svar, vi är bara helt öppna och nyfikna på den andres situation just nu. Det är inget som ska fixas eller tipsas om. Vi kans släppa kontrollen och bara vara där, det är då det blir ett äkta möte i närvaro. Så lyssna in till dagens avsnitt och få mina bästa tips till hur du kan utveckla mer närvaro och kärlek i dina relationer. Informationsmöte online 19/11 - Möt dig själv och led dig självFör dig som är nyfiken på att veta mer om hur jag jobbar med min Helhetsmodell, mina mindfulness meotder och hur jag jobbar med närvaro och kärek på utbildningar. Så vill jag uppmärksamma dig på att jag har ett informationsmöte tisdag den 19 november kl 19.00, som är online, där jag berättar mer om hur jag jobbar och även om min mest omfattande utbildning Möt dig själv och led dig själv, som startar i februari 2025.Läs mer och anmäl dig här: https://www.ingridthorngren.se/webinar Prova på dag 30/11 - Möt dig själv och led dig självFör dig som är nyfiken på den långa utbildnignen, men kanske inte har träffat mig tidigare, så kommer jag även ha en Prova på dag, ett Mindfulness Retreat, lördag den 30 november i Stockholm. För dig som vill möta mig och uppeva hur det är att jobba tillsmmans med mig. Läs mer här på länken eller på min hemsida: https://www.ingridthorngren.se/miniretreat Tack än en gång för att du är här och lyssnar, dela gärna podden till andra som behöver den, så hjälps vi åt att sprida mer närvaro och kärlek i värden. Så tills vi hörs igen tag hand om dig och din bästa vän – dig själv ❤️Hej så länge!

I sommar får alla flitiga A-kursare lite sommarlov och istället för tentor och plugg är det bara att lägga sig i hängmattan och fundera över livets stora frågor. Till vår hjälp har vi bjudit tillbaka tre tidigare gäster som utifrån sina vitt skilda forskningsfält delar med sig av tankar om existens, mening och autenticitet. I sjunde avsnittet av vår sommarserie tar vi oss an frågan: Är det viktigt att vara sitt autentiska jag?Gäster: Psykiatriker och forskare Christian RückNationalekonom och filosof Erik AngnerDoktor i evolutionär antropologi Caroline UgglaKlipp och musik:Walco - Store SpørsmålLaleh - Bara få va mig självFölj oss på instagram, @akursen_poddmail: akursenpodd@gmail.com Hosted on Acast. See acast.com/privacy for more information.

THE CROSS-EXAMINATION – Lawyers who are concerned about climate change increasingly want to see environmental values reflected in their practice. It can be difficult to advocate for change, especially for early career lawyers and those who feel that climate law is outside their expertise. But it turns out you don't have to be an environmental litigator or a managing partner to make a difference. In this episode, Becky speaks with two activists leading organisations that help provide lawyers and law students with tools to make a difference on climate change within the legal profession. Haley Czarnek, from Law Students for Climate Accountability (LSCA), and Ming Zee Tee, from Legal Voices for the Future (LVF), both believe that any lawyer has the skills and leverage to have a positive impact on the climate. Haley and Ming Zee discuss their views on the growing need to incorporate climate change issues into law school curriculums, the ethical duties of law firms in representing fossil fuel companies, the most exciting developments taking place in climate law, and the practical things those concerned about the environment can do to make a difference, no matter what your practice or stage of career. Guests:– Haley Czarnek, National Director, LSCA https://www.ls4ca.org – Ming Zee Tee, Chair, LVF https://www.lawsociety.org.uk/topics/climate-change/legal-voices-for-the-future

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Flora Curtis, barrister and member of the UK “Legal Voices for the Future” initiative.  Camila Bustos, Assistant Professor of Law at the Elisabeth Haub School of Law, Pace University (NY), and co-founder of the US body “Law Students for Climate Accountability”.   In this special episode we are joined by two guests.  Flora Curtis, a London-based barrister specialising in environmental law, and a member of “Legal Voices for the Future” (LVF), a learning forum acting as a voice for positive change about climate-related issues for the next generation of lawyers.  Professor Camila Bustos teaches on environment and climate justice and co-founded the “Law Students for Climate Accountability” initiative in the US to highlight the role lawyers can play on key environmental issues.  In this special episode we are joined by two guests. Flora Curtis, a London-based barrister specialising in environmental law, and a member of “Legal Voices for the Future” (LVF), a learning forum acting as a voice for positive change about climate-related issues for the next generation of lawyers.  Professor Camila Bustos teaches on environment and climate justice and co-founded the “Law Students for Climate Accountability” (LSCA) initiative in the US to highlight the role lawyers can play on key environmental issues.  Flora talks about how a barrister's work can focus on different aspects of environmental law, and the actual role a barrister can play in cases – including understanding important technical areas of environmental law, and discussing scientific findings with expert witnesses.  The challenge of the “cab rank” rule is considered, where barristers are under an obligation to offer representation to clients to enable access to justice, where climate-related ethical issues may arise from representing certain individuals or organisations.  Flora talks about the skills you use in such work, the importance of good research and questioning skills, and the need to have the confidence to challenge senior experts.  The work of LVF in running education sessions is highlighted, with topics ranging from climate litigation to “greenwashing” by corporations. Camila speaks about what led her to be one of the co-founders at Yale Law School of the LSCA initiative, now active across the whole US.  The disconnect between the rhetoric of law firms and their actions is explored, including how the group has put together an annual “Scorecard” to measure the performance of different law firms on climate-related issues – and also invites students, law firms and their clients to make a pledge on how they are contributing positively on climate-related issues.  Camila discusses the purpose of publishing this information, including the goal of empowering students to consider for which organisations they may like to work, and encourages students to remember what brought them to law in the first place as a field of study – remembering to keep their “Why?” and purpose front of mind as they build their careers.  Actions and resources for listeners:          Read the UK “Carbon Circle” report from the Law Students for Climate Accountability – what does this tell you about the Legal Industry's ties to the Fossil Fuel Industry? Also look at the organisation's latest “scorecard” for how major law firms rank in their activities related to fossil fuels: https://www.ls4ca.org/scorecard.         Follow the “Legal Voices for the Future” LinkedIn page to learn about their work, and recent knowledge sessions they have run.   

In one of the most powerful GAA Social podcasts to date, former Armagh manager Brian Canavan joins Thomas and Oisin. He talks football, one of the most high profile shootings in his bar during the Troubles- weeks before the signing of the Good Friday Agreement. Brian also talks living with Cancer, refereeing and perhaps unusually, there's plenty of laughs too. In 1998, best friends Damien Trainor and Phillip Allen were killed in a shooting in Poyntzpass. The LVF burst into the Railway Bar and shot dead the life-long friends. Brian Canavan owns the Railway Bar. Both Damien and Phillip were innocent locals, discussing the upcoming wedding of Phillip. Damien was due to be best man. It's one of the most high profile shootings during the troubles. It occurred weeks before the Good Friday Agreement was signed and notable because of David Trimble and Seamus Mallon, together visiting the homes of both victims. Canavan brings us back to that day. It's a remarkable moment in time. Canavan along with Brian McAlinden managed Armagh to back-to-back Ulster championships in 1999 & 2000. It's 23 years since Armagh beat Derry on that famous day at Clones. Oisin McConville scored the winning point after a dubious free was awarded. This week marks a special occasion for Brian. For the first time, he discusses his cancer treatment and on Wednesday May 4th will receive his final radiotherapy treatment. That's the plan! Brian was BBC co-commentator for almost 30 years, we reflect on those days, the battles when in charge of Armagh and a refreshing outlook on life. Brian and his wife Geraldine go away for a night once a week, date night and still the best of friends. Life lessons. It's an absorbing story of love, loss, football and life. It's the brilliant Brian Canavan on the GAA Social

Billy Wright, 'King Rat', was gunned down inside the Maze maximum security prison. How did the INLA manage to get a gun inside the jail and what was the LVF's bloody response? Host: Ciarán Dunbar. Guest: Belfast Telegraph security correspondent, Allison Morris. See omnystudio.com/listener for privacy information.

This week, please join author Michelle O'Donoghue and Associate Editor Parag Joshi as they discuss the article "Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease." 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, 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 and Director of the Poly Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, very interesting feature this week. Evolocumab, another application for that in patients with established atherosclerotic cardiovascular disease. But before we get to that feature discussion, how about we grab a cup of coffee and discuss some of the other very interesting articles in this issue? Dr. Carolyn Lam: Oh, I'd love that. And I'd like to go first, because Craig, have you heard of hybrid debranching repair? I know, I know. I had that same look, and can I tell you about it? Because I found it so interesting. Dr. Greg Hundley: Absolutely. Dr. Carolyn Lam: Now, the management of complex aortic aneurysmal disease involving the visceral vessels is challenging due to its very high morbidity and mortality. After four decades of experience in open repair, only a few centers worldwide report laudable results. And numerous factors limit total endovascular repair, including the access to devices, experience in deploying them, and several anatomical restrictions. So, hybrid debranching procedures were introduced for those patients who are unfit for the open or endovascular excluded patients. And while these have been developed, small series have only been done and revealed a wide range of short term results. So, today's paper is very important, and it's from Dr. Oderich from UT Memorial Herman Texas Medical Center and colleagues. It's a large multi-institutional study, which contains the five year outcomes in 200 patients offering greater clarity in the usefulness and limitations of these hybrid debranching repair procedures. What they found was that hybrid aortic debranching had a low early mortality when done in lower risk patients, but mortality remained very elevated in high risk patients. And so, this suggests that deep branching could be a good alternative in patients adequate for traditional open repair, although pulmonary complications are quite common. The bypass grafts to the visceral vessels had very good patency with a five year primary patency of 90%. Permanent spinal cord injury occurred in 6%, suggesting that deep branching in experienced centers may offer outcomes comparable to centers of excellence for open thoracoabdominal aortic aneurysm repair. Dr. Greg Hundley: Wow, Carolyn, very nice and so beautifully explained. Dr. Carolyn Lam: You know what, Greg? I'm on a roll and I'd like to tell you about one more, this time a preclinical study. First, a little bit about the background. You see, transplantation with pleuripotent stem cell derived cardiomyocytes, as we know, represents a very promising therapeutic strategy for cardiac regeneration. We even have first clinical studies in humans, but yet little is known about the mechanism of action underlying graft induced benefits. So in this paper from Dr. Weinberger from University Medical Center Hamburg in Germany and colleagues, they explored whether transplanted cardiomyocytes actually actively contribute to heart function by injecting these cardiomyocytes with an optogenetic off on switch in a Guinea pig cardiac injury model. Dr. Greg Hundley: Wow, Carolyn, this is so interesting. So what did they find? Dr. Carolyn Lam: So, light induced inhibition of endo-grafted cardiomyocyte contractility resulted in a rapid decrease in left ventricular function in about 50% of the animals that was fully reversible with the offset of photo stimulation. So in conclusion, this optogenetic approach demonstrated that transplanted cardiomyocytes can actively participate in heart function, supporting the hypothesis that the delivery of new force generating myocardium can serve as a regenerative therapeutic strategy. Dr. Greg Hundley: Oh wow, Carolyn. That was just fascinating. Such incredible preclinical science in our journal. Well, Carolyn, this next paper comes to us from the world of myocarditis. And Carolyn, it involves a population based cohort of 336 consecutively recruited patients with acute myocarditis enrolled in both London and Maastricht. And the authors, led by Dr. Sanjay Prasad from Royal Brompton Hospital, investigated the frequency and clinical consequences of dilated cardiomyopathy and arrhythmogenic cardiomyopathy genetic variants in this population based cohorts of patients with acute myocarditis. Now, Carolyn, all participants underwent targeted DNA sequencing for well characterized cardiomyopathy associated genes and their comparison to healthy controls, of which they had 1,053 that were sequenced on the same platform. Case ascertainment of their outcomes in England was assessed against their national hospital admission data, and the primary outcome was all cause mortality. Dr. Carolyn Lam: So what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So these authors identified for dilated cardiomyopathy or arrhythmogenic cardiomyopathy associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of desmoplakin truncating variants in those with normal LVF, and then titin truncating variants in those with a reduced LVF. So Carolyn, importantly, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing would be considered in patients with acute myocarditis to help reassure the majority of individuals that don't have one of these genes, while improving the management of those that do have one of the underlying genetic variants. Very interesting findings from the world of myocarditis. Dr. Carolyn Lam: Great. And a great clinical take home message. Thank you, Greg. Well, this next paper sought to investigate the influence of age on the diagnostic performance of cardiac troponins in patients presenting with suspected myocardial infarction. Dr. Atul Anand from the BHF Center for Cardiovascular Science and University of Edinburgh and colleagues did this by performing a secondary analysis of the high stakes stepped wedge cluster randomized control trial that evaluated the implementation of a high sensitivity cardiac troponin ISA in consecutive patients presenting with suspected acute coronary syndrome. Dr. Greg Hundley: Oh wow. Carolyn. Super interesting, and very applicable clinically. So what did they find here? Dr. Carolyn Lam: In older patients presenting with suspected MI, the majority of cardiac troponin elevations are explained by acute or chronic myocardial injury or type two MI. The specificity and positive predictive value of high sensitivity cardiac troponin to identify myocardial infarction decreases with age and is observed, whether applying sex specific or age adjusted 99th percentile diagnostic thresholds or a rolling threshold for the triage of patients at high probability of myocardial infarction. Serial troponin testing incorporating an absolute change in troponin concentration increased the discrimination for myocardial infarction in older adults. Dr. Greg Hundley: Oh wow, Carolyn. Such clinically applicable findings in this particular study, particularly when managing our aging population. Well, Carolyn, how about we discuss some of the other articles in this issue. And there's a very nice In-depth piece by our own Sami Viskin entitled “Arrhythmogenic Effects of Cardiac Memory.” And then, there's an exchange of letters by Drs. Giannitsis and Mueller regarding the article, “Unexpected Sensitivity Issue of Three High Sensitivity Cardiac Troponin I-Assays in Patients with Severe Cardiac Disease and Chronic Skeletal Muscle Diseases.” Dr. Carolyn Lam: Nice. There's also a Research Letter by Dr. Szendroedi on “Impaired Mitochondrial Respiration in Humans with Prediabetes: A Footprint of Prediabetic Cardiomyopathy.” And there's a CV case series by Dr. Kalra on very high cholesterol mimicking homozygous familial hypercholesterolemia. Interesting case. Well, I suppose that wraps it up. Let's go on to the feature discussion, shall we, Greg? Dr. Greg Hundley: You bet. Evolocumab. Welcome listers to this feature discussion on October 11th, and we're very fortunate today. We have with us Dr. Michelle O'Donoghue from Brigham Women's Hospital and Dr. Parag Joshi from UT Southwestern, the Associate Editor for this paper. Well, Michelle, can you describe for us some of the background information that went into the preparation of your study, and then what was the hypothesis that you wanted to address?   Dr. Michelle O'Donoghue: Sure. Happy to do so, and thank you for having me. So by way of background, the Fourier study, which was previously published in the New England Journal, compared Evolocumab to placebo in 27,000 plus patients with established atherosclerotic cardiovascular disease, and Evolocumab significantly reduced the risk of major adverse cardiovascular events. But, the follow up duration was relatively short. Median follow up was 2.2 years. So this was now an open label extension study to Fourier known as the Fourier OLE study that allowed an additional median follow up time of five years, during which time all patients were now treated with open label Evolocumab. T. He primary hypothesis that we were testing in this extension study was primarily to look at long term safety. We had limited data to really assure us of the safety of PCSK9 inhibitors over the course of several years. And so, safety was the primary hypothesis that we were testing, but also of course of key interest, during the parent Fourier study, we know that the benefit for cardiovascular risk reduction appeared to grow over time. So this was also an opportunity to see that pattern and to see whether or not there was in fact legacy effect for patients who were treated earlier with Evolocumab versus placebo. Dr. Greg Hundley: Very nice, Michelle. And so, sounds like we have a substudy of the Fourier trial. Can you describe for us a little bit more, for this substudy, your study population and your study design? Dr. Michelle O'Donoghue: Sure. So the patients enrolled in the open label extension were a subset of those who participated in the parent study. So as I previously mentioned, more than 27,000 participated in Fourier. It was a global study. For the open label extension, it was more than 6,500 patients who participated, and those were patients who were at sites in Europe and United States. And so, those patients were then followed on average for a meeting of five years. So that means that all together, patients who had been randomized to Evolocumab in the parent study had potentially more than eight years of drug exposure for us to examine safety. Dr. Greg Hundley: Very nice. And so, what did you find? Dr. Michelle O'Donoghue: Well, first, looking at the first hypothesis of safety, we saw no evidence that there was any increased risk of any adverse events of interest when it comes to PCSK9 inhibitors as a drug class, or achieving very low levels of LDL cholesterol. So there was no uptick in terms of neurocognitive events, the risk of diabetes. We do know that there was an increased risk of injection site reactions with the PCSK9 inhibitors, but not one that appeared to persist over time. So first was the safety, but importantly, I think that the more interesting results perhaps were those for MACE, for cardiovascular risk reduction. So we saw, even though all patients were being treated with open label Evolocumab during the extension phase, the benefit that was seen during the parent study persisted. So there was a 15% reduction in the primary outcome, a broad composite of cardiovascular events. There was also a 20% reduction in the triple composite of cardiovascular death, MI, or stroke. And then perhaps of the most interest to your listeners is that there was a 23% reduction in cardiovascular mortality, and that was not something that was seen in the parent study. It really took time for that mortality benefit to emerge. Dr. Greg Hundley: Very nice. Michelle. Just a couple quick clarification points. Did you see these effects in both men and women? And then was there any impact of age on those results? Dr. Michelle O'Donoghue: Great questions. Some of those subgroup analyses are still ongoing, but no, we did not see any evidence of effect modification at first pass. But again, we'll be continuing to dig into all potential subgroups. Dr. Greg Hundley: Very nice. Parag, I know you have many papers come across your desk. What attracted you to this particular manuscript? Dr. Parag Joshi: Yeah, thanks. And congratulations again, Michelle. It's a really phenomenal study, and the findings, as you highlighted, are just really impactful for the field. I think for our journal at circulation, this is a really high impact finding in terms of extending out, giving us a rigorous way to look at long term follow up for people on PCSK9 inhibitors and really reassure that there is safety there. And as you highlighted, a sustained reduction in LDL cholesterol, other compounds in the space, Bococizumab in particular, that there were induced antibodies against the monoclonal antibody, and that sustained response was not there. So I thought that was also really reassuring, that over the course of eight years, we see sustained LDL reduction. And with that, really reaffirming the idea that the longer you can reduce LDL, there's an associated reduction in events. And as you highlighted, the initial Fourier, there was some question about why there wasn't a CV death mortality signal while there was in the Odyssey outcome study and slightly different patient populations of course, but just really needed more time to start to tease that out. So all of this, I think this is the first that we're seeing this kind of long-term data on this impactful class of medications that really made this a fantastic manuscript for us at Circulation. Dr. Greg Hundley: Wow. Boy, Parag, I don't know that you could have stated that any better. So Michelle, looking forward, what is your group thinking? And then maybe just as your comment on the field in general, what do you think is the next study or series of studies that needs to be performed in this sphere of research? Dr. Michelle O'Donoghue: Well, I think he started to touch upon the areas of interest to us, is that I think that there are still many opportunities to answer more questions even within this existing data set. In particular, there was a dedicated neurocognitive substudy that was built into the parent study. And we also have that now through the extension period. So, that was a sort of more rigorous assessment of neurocognitive outcomes. And so, that's another analysis that we're going to be pursuing in the near future and I think is of potential key interest. And then beyond that, I think that the PCSK9 inhibitor class in general is just so interesting. There are additional compounds that are under study, such as small interfering RNA, so different mechanisms of getting to the PCSK9 protein. And I think it'll be reassuring to see whether or not they are consistent results, regardless of how you lower PCSK9, whether it translates into similar types of clinical benefit. So I think it's an exciting field. And then stay tuned. I think there'll be more to come. Dr. Greg Hundley: Parag, do you have anything to add? What do you see really as the next series of studies that might be performed here in this area of research? Dr. Parag Joshi: Yeah, I think Michelle hit the nail on the head that seeing confirmatory evidence here would be great. And then really, what's so exciting about this space is there's so much interest in ways to address this protein, including gene editing, vaccination against it. And now you're getting the necessary evidence that, hey, you can really suppress these levels in patients for years without concerning safety signals, at least from what we've seen so far. So that's more excitement as to long term ways to address cardiovascular risk. Dr. Greg Hundley: Wow. Well, listeners, we've been very fortunate today to have with us Dr. Michelle O'Donaghue from Brigham and Women's Hospital, and Dr. Parag Joshi from UT Southwestern as the Associate Editor of Circulation to really bring us these exciting results, highlighting that long term LDL-C lowering with Evolocumab was associated with persistently low rates of adverse events over eight years that did not exceed those observed in the original placebo arm during the parent Fourier study, and led to further reductions in cardiovascular events compared with delayed treatment initiation. Well, 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 ahajournals.org.

Billy Wright, 'King Rat', was gunned down inside the Maze maximum security prison. How did the INLA get a gun inside the jail and what was the LVF's bloody response? Host: Ciarán Dunbar. Guest: Belfast Telegraph security correspondent, Allison Morris.See omnystudio.com/listener for privacy information.

My son bust out his 2 front teeth!! click here for the video https://youtu.be/lVF-f6_2JhE --- Send in a voice message: https://anchor.fm/c4challenge/message

It's been 20 years since Sunday World journalist Martin O'Hagan was murdered on a Lurgan pavement as he walked home from a pub with his wife Marie. Known affectionately as Marty by his colleagues in the Belfast newsroom and an adored dad of three, he was just 51 when he became the only journalist to die as a result of The Troubles. His killing remains unsolved, but is believed to have been carried out by a team of LVF assassins acting on the dying wish of their twisted leader Billy Wright. But what was it like to lose a colleague and friend and how hard was it to continue working in a newsroom with an empty desk. Nicola Tallant talks to Sunday World reporter Richard Sullivan about the terrible night when a journalist became front page news, the reality of working in a warzone and the fading hopes of justice for Marty.

Pie Jurija Žigajeva jaunākajā “Tavs Gājiens” epizodē viesojās Latvijas Volejbola federācijas (LVF) valdes loceklis Kaspars Timermanis. Tika runāts par Latvijas izlasi Eiropas čempionātā, “Dinamo Rīga” variantu volejbolā, komentēšanu, pludmales volejbolu un daudz ko citu!

For this week's Feature Discussion, please join authors Igor Klem, Pasquale Santangeli, Mark N.A. Estes III, and Associate Editor Victoria Delgado as they discuss, in a panel forum, the articles: " The Relationship of LVEF and Myocardial Scar to Long-Term Mortality Risk and Mode of Death in Patients with Non-Ischemic Cardiomyopathy," "Prognostic Value of Non-Ischemic Ring-Like Left Ventricular Scar in Patients with Apparently Idiopathic Non-Sustained Ventricular Arrhythmias," and "Cardiac Magnetic Resonance Imaging in Nonischemic Cardiomyopathy: Prediction Without Prevention of Sudden Death." 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 in Richmond, Virginia. Well Carolyn, this week we've got another sort of double feature with a forum and our focus is going to be on myocardial scar that's observed with late gadolinium enhancement during cardiovascular magnetic resonance and the two author groups we'll be discussing the impact of that scar on the development of ventricular arrhythmias. But before we get to that, how about we grab a cup of coffee and jump into the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I certainly would. Although I have to say, can't wait for the double feature. I love those, and this is right up your alley too. All right. But first, the first paper I want to talk about provides new randomized trial information regarding the benefits of catheter ablation in atrial fibrillation in patients who also have heart failure. Now, this is a sub-study of the CABANA trial. Dr. Greg Hundley: So Carolyn, remind us a little bit about the CABANA trial first. Dr. Carolyn Lam: I thought you might ask. Well, CABANA randomized 2,204 patients with atrial fibrillation who were 65 years or older or less than 65 with one or more risk factors for stroke at, it was huge at 126 sites, and they were randomized to ablation with pulmonary vein isolation or drug therapy. Now of these, 35% of 778 patients had New York Heart Association Class II or higher at baseline, and really formed the subject of the current paper. Although this sub-study was not specifically designed to evaluate patients with heart failure with preserved ejection fraction, about 91% of the patients with a clinical diagnosis of heart failure participating in CABANA for whom such data on injection fraction were available, really had an ejection fraction of above 40% and fully 79% had an ejection fraction above 50%. So excitingly, this is really majority talking about, have HFpEF. Now, what did they find well in patients with New York heart Association Class II or III heart failure at trial entry, most of whom did not have a reduced ejection fraction. Dr. Carolyn Lam: There was substantial clinical outcome benefits with the ablation over drug therapy with a 36% relative reduction in the primary composite endpoint of death, disabling stroke, serious bleeding or cardiac arrest. Benefits were evident for both all-cause mortality and atrial fibrillation reduction. However, the effects on heart failure hospitalization were small and not significant. Authors also caution that these results should not be viewed as practice changing until they are reproduced in a confirmatory trial of ablation in the same population. And this is beautifully discussed in an editorial by Lynda Rosenfeld and Alan Enriquez from Yale University School of Medicine. Dr. Greg Hundley: Oh, wow. Thanks Carolyn. Well, my first paper comes from the world of basic science and it's from Professor Thomas Braun, from the Max Planck Institute for Heart and Lung Research. So Carolyn, vascular smooth muscle cells show a remarkable phenotypic plasticity allowing acquisition of contractile or synthetic states, but critical information is missing about the physiological signals that promote formation and maintenance of contractile vascular smooth muscle cells in vivo. So BMP-9 and BMP-10 are known to regulate endothelial quiescence after secretion from the liver and right atrium. And these investigators are studied the role of BMP-9 and 10 for controlling formation of contract, all vascular smooth muscle cells. Dr. Carolyn Lam: Greg, talking about vascular smooth muscle cells always reminds me of their role in pulmonary hypertension, am I right? Dr. Greg Hundley: Yes, Carolyn. So these investigators found that in mouse models, BMP-9 and BMP-10 act directly on vascular smooth muscle cells for induction and maintenance of their contractile state, and surprisingly the effects of BMP-9 and 10 in vascular smooth muscle cells are mediated by different combinations of BMP type 1 receptors in a vessel bed specific manner. And therefore, just as you suggest, Carolyn, these results may offer new opportunities to manipulate blood pressure in the pulmonary circulation. Dr. Carolyn Lam: Thank you, Greg. Well, my next paper provides the first proof of principle of gene therapy for complete correction of Type 1 Long QT syndrome. Dr. Greg Hundley: Ah, so tell us a little bit about Type 1 Long QT syndrome, Carolyn. Dr. Carolyn Lam: Okay. Well Type 1 long QT syndrome is caused by loss of function variants in the KCNQ1 and coded potassium channel alpha sub-unit. And that is essential for cardiac repolarization providing the slow delayed rectifier current. Now no current therapies target the molecular cause of this Type 1 long QT syndrome. Well, this study from Dr. Michael Ackerman colleagues from Mayo Clinic Rochester really established a novel dual component suppression and replacement KCNQ1 gene therapy approach for Type 1 long QT syndrome. And it's the type that contains the KCNQ1 short hairpin RNA to suppress endogenous expression and a codeine altered short hairpin RNA immune copy of this KCNQ1 for gene replacement. Dr. Carolyn Lam: So this very novel approach rescued the prolonged action potential duration in inducible pluripotent STEM cell cardiomyocytes derived from four patients with unique Type 1 Long QT syndrome, causative, KCNQ1 variants. So it's super cool. Just go have a look. Dr. Greg Hundley: Well, thanks Carolyn. Dr. Carolyn Lam: I want to also tell you about other things in the mail bag. We have ECG Challenge by Dr. Dai on “Severe Arrhythmia Caused by a Chinese Herbal Liqueur. What's the Diagnosis?” I'm not going to tell you. You have to go see. We have Dr. Karen Sliwa writing a beautiful Joint Opinion paper from the World Heart Federation and American College of Cardiology, American Heart Association, and European Society of Cardiology on "Taking a Stand Against Air Pollution, the Impact on Cardiovascular Disease." Dr. Greg Hundley: Well, thanks Carolyn. So I've got a couple other articles. First Professor Yacoub has a global rounds describing and working towards meeting the challenges of improving cardiovascular health in Egypt. Those are really interesting features to learn about cardiovascular care worldwide. Next there's an In Depth article by Professor Thum entitled, "Therapeutic and Diagnostic Translation of Extracellular Vesicles in Cardiovascular Diseases, Roadmap to the Clinic." And then finally, a Research Letter from Dr. Bottá entitled, "Risk of Coronary Artery Disease Conferred by Low Density Lipoprotein Cholesterol Depends on Apologetic Background." Well, Carolyn, what a great issue and how about now we proceed on to that double feature? Dr. Carolyn Lam: Oh, I can't wait. Thanks Greg. Dr. Greg Hundley: Well, listeners, we are here for a really exciting feature discussion today that's going to focus on imaging, in particular magnetic, resonance imaging, and some new findings in that era and how those findings may pertain to ventricular dysrhythmias. With us today, we have Dr. Igor Klem from Duke University who will be discussing a paper, Dr. Pasquale Santangeli from University of Pennsylvania, our own associate editor, Dr. Victoria Delgado from Leiden and an editorialist, Dr. Mark Estes from UPMC in Pittsburgh. Welcome to all of you. Well, Igor, we're going to start with you. Could you tell us what was the hypothesis for your study and what was your study population in study design? Dr. Igor Klem: Yes. Good morning, Greg and thanks for the invitation. We wanted to know if you have a patient who you diagnosed with non ischemic cardiomyopathy based on clinical grounds and you refer him for a cardiac MRI study with contrast, what is the additional information that you get from the MRI study? And so we wanted to compare, and that's primarily related to the findings on scar imaging with late gadolinium enhancement. And we wanted to compare that to one of the most robust clinical parameters in cardiology, which is left ventricular ejection fraction, and in particular using a cutoff of 35%, which somehow in our clinical management has sort of as established as a break point for many clinical decisions. Dr. Igor Klem: And so we created a registry among three centers of patients who undergo a cardiac MRI study, where we found an LVEF of less than 50% and we followed them for a number of outcomes. One is all caused death. And then we wanted to separate a little bit the events into those who have cardiac mortality to look at a little epidemiology because in those patients, we have two major adverse events: one as heart failure related mortality. One is arrhythmia related mortality. Dr. Greg Hundley: And how many subjects did you include? Dr. Igor Klem: We included about a thousand patients from three centers and coming to the major findings of our study, we found that both left ventricular ejection fraction, as we know, is a robust marker of all cause mortality and cardiac death. And so it was the presence of myocardial scar on cardiac MRI. But the major difference was in relation to the arrhythmic events. We founded left ventricular ejection fraction in particular, when we use the 35% cutoff actually had very little predictive power to inform us who is at risk of arrhythmic events. In contrast, there was a very strong and robust relationship or multiple statistical methods to stratify patients who are at risk for sudden cardiac death, appropriate ICD shock, as well as arrhythmic cardiac death. Dr. Greg Hundley: Very good. Well, Pasquale understand you also performed a research study utilizing cardiovascular magnetic resonance. Could you describe for us your hypothesis as well as what was your population and your study design? Dr. Pasquale Santangeli: Thank you, Greg. And of course, thanks to the editor for the interest in our paper. I need to thank also the first call authors Daniele Muser and Gaetano Nucifora for putting together a registry of 70 institutions throughout the U.S., Europe, and Japan and the our hypothesis came from a clinical need. We do know that patients with idiopathic ventricular re we ask, which includes not sustain a weakness like PVCs or non-sustained VT. Very few of them, but there is a group of them that have a higher risk of ending malignant and up comes in terms of your ethnic events over follow-up. And prior studies have shown that by doing an MRI and showings and the detecting scar related announcement, there is an increase with how we make events of a follow-up. However, if you do look at those studies late, an answer's been reported in up to 70% of these patients, which you never view is a highly practical way of re-stratifying these patients, because you have a risk factor that is present 70% of those, then it's hard to use it for clinical decision-making. Dr. Pasquale Santangeli: So in this registry, which you put it again at 686 patients with panel data idiopathic, not sustained ventricular arrhythmias, which were defined by a normal WBC gene status, a normal echocardiogram and a normal stress test. We looked at whether there is a specific pattern of late announcement. So how basically I believe lands, and it looks on the MRI, they may predict better or outcomes over follow-up. And again, we use a composite and Pauline the full cost mortality, but associated cardiac arrest due to ventricular fibrillation or a hemodynamically unstable BP, or in a subgroup of patients that underwent ICD therapy. We also looked at, I approve SED shocks. Dr. Pasquale Santangeli: The groups were divided in three different categories. The first one, which is a larger group of 85% of patients and no late announcement. The second group, the one with late announcement, which represents the remaining 50% of 15% of patients, we divided it into a ring light pattern, which was defined as that word says, as a ring like distribution of the lead announcement in the mid-market segments, which involves a three consecutive continuous segments in a short axis view. It looks like really at least half the ring or three-quarters of the ring. Dr. Pasquale Santangeli: And the other group is the one that had the leader announcement without a ring light pattern. And it's interesting that the third and the latest announcement was not that similar between the ring light and the one without ring light late announcement. What we did find though for our follow-up the patient with a ring light pattern, a significantly higher rate of the primary composite endpoint, which happened in the median follow-up about 61 months so it was quite long. And the composite outcome occurred in 50% of patients in the ring light group versus 19% in the no ring light a positive announcement group and a 0.3%. So really, really rare in patients. So then concluded that of course, late announcement does provide some information in general, particularly the type of announcement that increases the risk significantly. Probably although this has to be confirmed prospective fashion patient with a ring light pattern may benefit from other forms of interventions, including potentially defibrillator therapy in a prophylactic fashion. Dr. Greg Hundley: Very nice. So now listeners, we're going to turn to our associate editor. One of the imaging experts here at Circulation, Dr. Victoria Delgado. Victoria, you see a lot of papers come across your desk and as an imaging expert, what attracted you to these two papers? And what do you think are their significance? Dr. Victoria Delgado: Thank you, Greg. I think that these two papers are important because right now, if we follow the clinical guidelines, we decide implantation. For example, of an ICD based on the ejection fraction, and we see that in many patients based on ejection fraction, they may not benefit ever from an ICD because they don't have arrhythmias. What other patients who do not meet the criteria often injection fraction below 35%. They may have still arrhythmias. So the article by Igor highlights the relevance of the amount of burden of late government Huntsman with CMR, in patients with non ischemic cardiomyopathy, which are sometimes very challenging patients on how to decide when we implant an ICD or not. We need sometimes to base the decision on genetics. Dr. Victoria Delgado: If we have an on the other hand, the paper of Pasquale, these were patients with normal echocardiogram. So what patient, having arrhythmias where we don't see on echocardiogram, that is the first imaging technique that we usually use to evaluate these patients. We don't see anything, but CMR can give us more information in terms of structural abnormalities and particularly not only the burden of scar, but also the pattern of the scar. And we have seen in other studies that for example, not only for ICD implantation, but for ventricular tachycardia ablation. The characteristics of that scar and some areas where these are short of panel that can be targeted for that ventricular tachycardia ablation can lead to much more precise treatment if you want of these patients. Dr. Greg Hundley: Thank you, Victoria. So it sounds like listeners we're hearing late gadolinium enhancement, regardless of EF could be forecasting, future arrhythmic events. And then also the pattern of late gadolinium enhancement, where contiguous segments in a ring-like fashion may also offer additional prognostic information. Well, now we're going to turn to our editorialists and as you know, listeners at Circulation, we'll bring in an editorialist to really help put things together and uniquely here today, we have Dr. Mark Estes, who is really not an imager per se, but like many of us uses the information from imaging to make clinical decisions. Mark, how do you see this late gadolinium enhancement as perhaps a new consideration for placement of devices? Dr. N.A. Mark Estes: Greg, that's one of the key questions. There's no doubt, not only based on these two studies, which extend our prior information about LGE and patients with valid and non ischemic cardiomyopathies that scar burden is important in predicting not only total mortality, but arrhythmic events. All of the criteria that were used in the original ICD studies, which include the definite, the Skuid half Danish and made it our it trials use only ejection fraction and functional status, no imaging. These are legacy trials. Now, many of them, a decade or more older. And the treatment of advanced heart failure has progressed to the point that the total mortality is dramatically lower than it was at the time of these studies. In some instances down to 4 or 5% per year. The studies are important in that they identify a subgroup of patients with low ejection fractions, less than 35%, who might qualify for ICDs, who are unlikely to benefit. Dr. N.A. Mark Estes: They also identify a group of patients with preserved ejection fraction greater than 35%, less than 50 in whom the risk of sudden death may be substantial. And it extends prior observations about patchy, mid Meyer, cardio wall fibrosis, subendocardial, subepicardial and important ways. But the key issue here, and it was alluded to with Pasquale's comments about prospective validation, is that when one has a risk stratifier and identifies a high risk population that has to be linked to an unequivocal therapy, it improves survival. And we don't have that link quite yet. Dr. N.A. Mark Estes: Prospective randomized trials are unlikely to be done in the low ejection fraction because they would probably be considered unethical. Given the trials that have shown the benefit you can't randomize to defibrillator versus an implantable loop recorders. I think the future really lies in risk stratification for people with preserved ejection fractions greater than 35%, less than 50 using LG in that patient population. Currently, I think the best information we can give to clinicians is to stick with the AHA guidelines, which is PF less than 35% with dilated, nonischemic class II symptoms who have had optimal medical therapy for at least three months using perhaps in that patient population LGE for shared decision-making in patients about the magnitude of the risk. And I think that's as far as we can go pending future studies, and there is one which we can discuss later on the CMR study at just that preserved ejection fraction LGE randomizing to defibrillator versus ILR. Dr. Greg Hundley: Thank you, Mark. So listeners just really quickly, let's go back to each of our experts and ask them, you know, in 20 seconds, Igor, Pasquale, Victoria, and Mark, what's the next study that needs to be performed in this space? Igor, we'll start with you. Dr. Igor Klem: Well, number one, following on Mark's comment on the less than 35% population, I think that it's unlikely that they're randomized clinical trial is ethical in this population, but we may consider a wealth of registry data by now that shows that there is a subgroup of patients who have a lower risk or lower benefit from an ICD. I think in the preserved ejection fraction above 35%, maybe up to 45%, 50%. That's an interesting study that's coming up. Maybe there's more trials that can provide us that robust information that we need today in order to change the guidelines to risk stratify, not based on the LVF, but on the presence of scar or maybe subgroups of scar. Dr. Greg Hundley: Pasquale? Dr. Pasquale Santangeli: Yes. So I think of course, one of the major studies is the one already alluded by this, which is a prospective study that links as specific therapy like ICD or even additional risk factors like we've been using program's stimulation some of these patients to further risk for the five to see what they can benefit. Dr. Pasquale Santangeli: Based another one that I think is important for the study that we did is a mechanistic more study to understand why the ring light pattern was there, as opposed to other patterns. We do believe we think that some of these patients may have an initial form of lb dominant arrhythmogenic paramount. There wasn't really a detective before and ran. Now, if we actually extending our study and have a registry to try to screen also the family members or patients with ring light pattern to understand whether there is a familiar component to it, because really we do not see this type of pattern that commonly and it'd been associated with lb dominant. Magnetic kind of alpha in some others, small studies. Dr. Pasquale Santangeli: So that's the other part to dig in a little bit more into the field type for these patients to understand why one pattern versus another happens and whether that gets main to, to explain why there's a higher risk in one population versus another. Dr. Greg Hundley: Victoria. Dr. Victoria Delgado: Yeah. Following what has been said. I think that from the imaging point of view, we are always criticizing in a way that we increase the burden or the cost of healthcare. But I think that these studies or any randomized study where MRI or echo is used in order to design a therapy and show the value of using that imaging technique to optimize the health care costs is important. So I will not add much on which sort of populations, but probably patients within non ischemic cardiomyopathy with preserved ejection fraction that do not fulfill the recent scores, for example, in hypertrophic cardiomyopathy to be implanted with an ICD. But probably if we see a lot of scar on a AGE where specific patterns that can help to decide which are the patients that have benefited from an ICD implantation, for example. Dr. Greg Hundley: Thank you. And finally Mark. Dr. N.A. Mark Estes: But I think all the major points have been hit here. And unfortunately we have a bit of a dilemma. And that dilemma is that these legacy trials for ICDs, which selected based on low ejection fraction and functional class II were done at a time when contemporary heart failure treatment was not as good as it currently is pharmacologically. And it's been reflected with a lower total mortality. When the mortality in this patient population gets down to the 4 and 5% per year, it's unlikely that any intervention for prevention of sudden death is going to impact on that total mortality. Dr. N.A. Mark Estes: So I do think that the registries hold a lot of promise, giving us insights into the subgroup of patients that previously would have been selected for defibrillators who may not have as much benefit or who may benefit the most. And I think that they will play an important part in perhaps refining the risk stratification with greater sensitivity and specificity in the patient population, less than 35%. I think the CMR guide trial is going to be a critical trial and looking at ICDs in the patient population between 35 and 50%, but we need to be mindful of one thing. And that in the Danish trial, they get a sub study looking at about 240 patients using LGE. And they found that ICD in patients with LGE that was positive, did not make a difference in survival or total mortality. So again, we need to get the data. I think the best clinical practice has come out of the best clinical evidence. You'll clearly be limitations to what we can do, but I think in the future, we'll have much better data to make these judgment calls. Dr. Greg Hundley: Very good. Well listeners, we want to thank our panelists, Dr. Igor Clem, Pasquale, Santangeli, Victoria Delgado, and Dr. Mark Estes for this wonderful discussion related to magnetic resonance imaging, late gadolinium enhancement, and how it may be useful in identifying those at risk for future arrhythmic events. On behalf of both Carolyn and myself, 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, 2021.  

Paul J. Wang: Welcome to the monthly podcast On the Beat for Circulation: Arrhythmia and Electrophysiology. I'm Dr. Paul Wang, editor-in-chief with some of the key highlights from this month's issue. In our first paper, Danielle Haanschoten, Hein Wellens and Associates aim to examine survival benefit of prophylactic implantable cardioversion defibrillator (ICD) implantation in early selected high-risk patients with primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). A randomized, multicenter, controlled trial compared ICD versus conventional medical therapy in high-risk primary PCI patients based on one of the following factors: Left ventricular ejection fraction (LVF) less than 30% within four days of STEMI, primary ventricular fibrillation, Killip class 2 or greater and/or TEMI flow less than three after PCI. ICD was implanted 30 to 60 days after MI, myocardial infarction, primary endpoint was all cause mortality three years of follow-up. The trial was prematurely ended after inclusion of 266 patients, 38% of the calculated sample size. Additional survival assessments was performed in February 2019 for the primary endpoint. A total of 266 patients, 78.2% male with a mean age of 60.8 years were enrolled. 131 were randomized to the ICD arm and 135 patients to the control arm. All cause mortality was significantly lower in the ICD group, five versus 13, hazard ratio of 0.37 after three years follow-up. Appropriate ICD therapy occurred in nine patients at three years follow-up, 5 within the first eight months after implantation. After median long-term follow-up of nine years, total mortality (18% versus 38%, hazard ratio of 0.58) and cardiac mortality (hazard ratio of 0.52) was significantly lower in the ICD group. Non-cardiac death was not significantly different between the groups. LVEF increased 10% or more in the 46.5% of patients during follow-up and the extent of improvement was similar in both study groups. The authors concluded that in this prematurely terminated and thus underpowered randomized trial early prophylactic ICD implantation demonstrated lower total and cardiac mortality in high-risk STEMI patients treated with primary PCI.   In our next paper Felipe Bisbal, Eva Benito and Associates aim to test the efficacy of ablating, cardiac magnetic resonance, CMR detected atrial fibrosis plus pulmonary vein isolation (PVI). This was an open label, parallel group, randomized controlled trial. Patients with symptomatic drug refractory AF paroxysmal or persistent undergoing first or repeat ablation were randomized one-to-one basis to receive PVI plus CMR-guided fibrosis ablation, the CMR group or PVI alone, the PVI alone group. The primary endpoint was a rate of recurrence greater than 30 seconds at 12 months of follow-up using a 12-lead ECG and Holter monitoring at 3, 6 and 12 months. The analysis was conducted by intention to treat. In total 155 patients, 71% male, age 59, CHADS2-VASc 1.3, 54% paroxysmal AF were allocated to the PVI group alone (n=76) or CMR group(n=79). First ablation was performed in 80% and 71% in the PVI alone and CMR groups respectively. The mean atrial fibrosis burden was 12%, only approximately 50% of patients had fibrosis outside the pulmonary vein area. 100% and 99% of patients received the assigned intervention in the PVI alone and CMR group. Primary outcome was achieved in 21 patients (27.6%) in the PVI alone group and 22 patients (27.8%) in the CMR group (Odds ratio 0.01, P=0.976). There was no differences in the rate of adverse events, three in the CMR group and two in the PVI alone group. The authors concluded that a pragmatic ablation approach targeting CMR detected atrial fibrosis plus PVI was not more effective than PVI alone in an unselected population undergoing AF ablation with low fibrosis burden.   In the next paper, Vivek Reddy and Associates tested a novel neuromodulation therapy of stimulation of epicardial cardiac nerves passing along the posterior surface of the right pulmonary artery. 15 subjects admitted for defibrillator implantation (ejection fraction≤35%) on standard heart failure medications were enrolled. Through femoral arterial access, high fidelity pressure catheters were placed in the left ventricle and aortic root. After electro anatomic rendering of the pulmonary artery and branches, either a circular or basket electrophysiology catheter was placed in the right pulmonary artery to allow electrical intravascular stimulation at 20 hertz, 4 ms pulse width, and less than or equal to 20 milliamperes. Changes in the maximum positive dP/dt, the dP/dtMax indicated change in ventricular contractility. Of 15 enrolled patients, five were not studied due to equipment failure or abnormal pulmonary artery anatomy. In the remaining patients dP/dtMax increased significantly by 22.6%. There was also a significant increase in maximum negative dP/dt, dP/dtMin, mean arterial pressure, systolic pressure, diastolic pressure, and left ventricular systolic pressure. There was no significant change in heart rate or left ventricular diastolic pressure. In this first-in-human study, the authors demonstrated that in humans with stable heart failure, left ventricular contractility could be accentuated without an increase in heart rate or left ventricular filling pressures.   In our next paper, Jorge Romero, Luigi Di Biase, and Associates, in their study investigated the incremental benefit of left atrial appendage electrical isolation (LAAEI) in patients undergoing catheter ablation for nonparoxysmal atrial fibrillation (AF). Propensity score-matched analysis was performed using a prospective registry database from 2010 to 2014. All patients in the LAAEI group were matched based on baseline characteristics, echocardiographic parameters, and procedural ablation techniques. Authors identified 1842 patients who underwent catheter ablation for nonparoxysmal atrial fibrillation. Propensity score matching yielded 1092 patients, 546 with LAAEI, and 546 without LAAEI. At five years follow-up, overall freedom from all arrhythmia recurrence, off-antiarrhythmic drugs, in patients who underwent LAAEI was 68.9% versus 50.2% in those who underwent standard ablation (p

This episode is based around the life of Billy Wright. He was one of the most prominent loyalist icons involved in the troubles. After waging war on the Nationalists and then clashing against the UVF, Wright went on to found his own paramilitary group called the Loyalist Volunteer Force, or LVF. There was a target on his head for many years, but no one expected that it would be inside the Maze Prison, where Wright would meet his end. SOURCES:Excellent BBC Documentary featuring Wright:https://www.youtube.com/watch?v=JDcehKOuLWI&t=7s&ab_channel=Monkiesocks56Interview with Billy Wright shortly before his death:https://www.youtube.com/watch?v=SnaT90pHvPk&ab_channel=ULETLegacyArchiveJohnny Adair talking about Billy Wright:https://www.youtube.com/watch?v=N_6VA4BoKw8&ab_channel=AnythingGoesWithJamesEnglishArticle about Wright's murder:https://magill.ie/politics/murder-king-rat-billy-Wright Another (bad quality) interview with Wright:https://www.youtube.com/watch?v=IuHcCX1A3xk&ab_channel=swiftubag1001BBC article about the life of Wright:https://www.bbc.com/news/uk-northern-ireland-11112737Inquiry findings: https://www.bbc.co.uk/news/uk-northern-ireland-11306492 See acast.com/privacy for privacy and opt-out information.

Paul J. Wang: Welcome to the monthly podcast, On the BEAT, for Circulation: Arrhythmia and Electrophysiology. I'm Dr. Paul Wang, Editor in Chief, with some of the key highlights from this month's issue. Paul J. Wang: Albert Feeny and Associates used unsupervised machine learning of electrocardiogram [ECG] waveforms to identify cardiac resynchronization therapy [CRT] subgroups to differentiate outcomes beyond QRS duration and left bundle branch block. They retrospectively analyzed 946 CRT patients with conduction delay. Principal component analysis [PCA] dimensionality reduction obtained a 2-dimensional representation of pre-CRT 12-lead QRS waveforms. K-means clustering of the 2-dimensional PCA representation of 12-lead QRS waveforms identified two patient subgroups [QRS PCA groups]. Vectorcardiographic QRS area was also calculated. They examined two primary outcomes: (1) composite endpoint of death, left ventricular assist device, or heart transplant, and (2) degree of echocardiographic left ventricular ejection fraction [LVEF] change after CRT. Compared to QRS PCA group 2 (n = 425), Group 1 (n=521) had a lower risk for achieving the composite endpoint (hazard ratio of 0.44, P < 0.001) and experienced greater mean LVEF improvement (11.1% versus 4.8%, P < 0.001), even among left bundle branch block patients with QRS duration, 150 milliseconds or greater (hazard ratio 0.45, P < 0.001; mean LVF change 12.5% versus 7.3%, P=0.001). A stratification scheme combining QRS area and QRS PCA group identified left bundle branch block patients with similar outcomes as non left bundle branch block patients (hazard ratio 1.32, mean difference LVEF change 0.8%). That stratification scheme also identified left bundle branch block patients with QRS duration less than 150 ms is comparable outcomes to left bundle branch patients with QRS duration 150 ms or greater (hazard ratio 0.93, mean difference in LVF change -0.2%). The authors concluded that unsupervised machine learning of ECG waveforms identified CRT subgroups with relevance beyond left bundle branch block and QRS duration. Paul J. Wang: In our next paper, Julie Shade, Rheeda Ali and Associates combined machine learning [ML] and personalized computational modeling to predict, prior to pulmonary vein isolation [PVI], which patients are most likely to experience atrial fibrillation [AF] recurrence after PVI. The single center retrospective proof of concept study included 32 patients with documented paroxysmal AF who underwent PVI and had pre-procedural late gadolinium enhanced magnetic resonance imaging [LGE MRI]. For each patient, a personalized computational model of the left atrium simulated AF induction via rapid pacing features were derived from pre-PVI LG MRI images and from results of simulations [SIM] AF. The most predictive features used to input to a quadratic discrimination analysis ML classifier, which was trained, optimized, and evaluated with a 10-fold nested cross validation to predict the probability of AF recurrence post PVI. In the cohort, the ML classifier predicted probability of AF recurrence with an average validation, sensitivity, and specificity of 82% and 89% respectively, and a validation AUC of 0.82. Dissecting the relative contributions of simulations SIM AF and raw images to the predictive capability of the ML classifier, they found that only when features from simulation SIM AF were used to train the ML classifier, its performance retained similar (validation AUC equals 0.81). However, when only features classified from raw images were used for training, the validation AUC significantly decreased (0.47). Paul J. Wang: In our next paper, Sarah Vermij and Associates examined sodium channel NaV 1.5 localization and function mutations in the gene and coding the sodium channel NaV 1.5 caused various cardiac arrhythmias. The authors use novel single-molecule localization [S-M-L-M] and computational modeling to define nanoscale features of NaV 1.5 localization and distribution at the lateral membrane [L-M], the LM groove, and T-tubules in cardiomyocytes from wild-type (N=3), dystrophin-deficient (mdx; N=3) mice, and mice expressing C-terminally truncated NaV 1.5 (ΔSIV; N=3). The authors assessed T-tubules sodium current by recording whole-cell sodium currents in control (N=5) in detubulated (N=5) wild-type cardiomyocytes. The authors found that NaV 1.5 organizes as distinct clusters in the groove and T-tubules which density, distribution, and organization partially depend on SIV and dystrophin. They found that overall reduction in NaV 1.5 expression expressed in mdx and ΔSIV cells result in a non-uniform distribution with NaV 1.5 being specifically reduced at the groove ΔSIV and increased in T-tubules of mdx cardiomyocytes. A T-tubules sodium current could, however, not be demonstrated. The authors concluded that NaV 1.5 mutations may site-specifically affect NaV 1.5 localization and distribution at the lateral membrane and T-tubules, depending on site-specific interacting proteins. Paul J. Wang: In our next paper, Sharan Sharma, Mohit Turagam, and associates studied strategies to improve patient comfort related to pericardial access. They conducted a multi-centered retrospective study, including 104 patients who underwent epicardial ventricular tachycardia [VT] ablation and Lariat left atrial appendage occlusion. They compared 53 patients who received post-procedural intrapericardial liposomal bupivacaine (LB)+oral colchicine (LB group) and 51 patients who received colchicine alone (non-LB group). Lyposomal bupivacaine was associated with significant lowering of median pain scale at 6 hours (1.0 versus 8.0, P

This week’s episode features author Karolina Szummer and Associate Editor Emmanouil Brilakis as they discuss the article "Comparison Between Ticagrelor and Clopidogrel in Elderly Patients with an Acute Coronary Syndrome: Insights from the SWEDEHEART Registry." 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, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, this week's feature article, we're going to investigate antiplatelet therapy use, but in older patients, as opposed to those that are middle-aged, and have sustained a prior acute myocardial infarction. But, before we get to that, how about we grab a cup of coffee and jump into the other papers in the issue? Dr Carolyn Lam: Absolutely, Greg. I've got my coffee right here, and I really want to start with a paper that adds to our understanding of, guess what, the sodium=glucose cotransporter 2 inhibitors, SGLT2 inhibitors, and their diuretic and natriuretic effects in combination with loop diuretics. Of course, a clinically really important question since now we know that SGLT2 inhibitors improve outcomes in patients with heart failure in whom they are likely to be co-prescribed with a loop diuretic. So, Professor Chim Lang from University of Dundee and his colleagues performed the RECEDE-CHF trial, which was a randomized double-blind placebo-controlled crossover trial of 23 patients with type 2 diabetes and HF REF taking regular loop diuretics who were randomized to the SGLT2 inhibitor empagliflozin 25 milligrams once daily or placebo for 6 weeks with a 2-week washout period. The primary outcome was change in 24-hour urine volume from baseline at week 6. Dr Greg Hundley: So, empa versus placebo. What did they find? Dr Carolyn Lam: In patients with heart failure and type 2 diabetes taking a regular loop diuretic, empagliflozin caused a significant increase in urine volume at both day 3 and week 6, compared to placebo, as well as empa also caused a significant increase in electrolyte-free water clearance. Though there was a small non-significant increase in natural uresis with empagliflozin at day 3, this was absent by week 6. These results suggest that empagliflozin may have an advantageous diabetic profile in patients with type 2 diabetes and heart failure in addition to loop diuretics, with only a short transient natriuresis. Dr Greg Hundley: Very nice, Carolyn. Great information. Diuretics, heart failure reduced ejection fraction, and empagliflozin. Well, my clinical paper comes from Dr Renato Lopes from Duke University Medical Center, and this is a sub study from the ISCHEMIA trial that evaluates whether an initial invasive strategy in patients with stable ischemic heart disease and at least moderate ischemia improves outcomes in patients with a history of heart failure or left ventricular dysfunction when the EF is greater than 35%, but less than 45%. Dr Carolyn Lam: Aw, that mid-range ejection fraction. Favorite topic. So, Greg, what did they find? Dr Greg Hundley: Those with heart failure and left ventricular dysfunction randomized to the invasive versus the conservative strategy had a lower rate of the primary outcome, 17% versus 29%. Whereas those without heart failure and left ventricular dysfunction did not, 13% versus 14%. A similar differential effect was seen for the primary outcome, all-cause mortality and cardiovascular mortality, when invasive versus conservative strategy associated outcomes were analyzed with LVF as a continuous variable for those with and without prior heart failure. Dr Carolyn Lam: Wow, that is clinically important, Greg. So, can you summarize our take home message? Dr Greg Hundley: Well, Carolyn, ischemia trial participants with stable ischemic heart disease and at least moderate ischemia with a history of heart failure or LV dysfunction, were at increased risk for the primary outcome. And in this small high-risk subgroup with heart failure and an ETF between 35% and 45%, an initial invasive approach was associated with a better event free survival. This result should really be considered for hypothesis generation and future studies. Dr Carolyn Lam: Greg, for the next paper, do you remember hydrogen sulfide? The stuff we learned about in school. It's the gas with that characteristic foul odor of rotten eggs. Well, guess what? This whole paper is about hydrogen sulfide, and in the body, it actually has antihypertensive and anti-inflammatory effects, and its endogenous generation key enzyme is cystathionine gamma lyase, or CSE, and that's expressed in CD4+ T cells. So today's paper provides insights into how all of these players work together in the development of hypertension. To investigate the pathophysiological relevance of this CSE hydrogen sulfide system, co-corresponding authors, Doctors Geng and Cai from Fuwai hospital and Chinese Academy of Medical Sciences, Peking University Medical College, as well as Dr Xu from Peking University Health Science Center in Beijing. Well, they and their coauthors performed elegant experiments involving peripheral blood lymphocytes, isolated from hypertensive patients or spontaneously hypertensive rats. They also looked at mice with CSE-specific knockout in T cells, and CD4 null mice. Dr Greg Hundley: Well, Carolyn, what did they find? Dr Carolyn Lam: Well, they found that endogenous cystathionine gamma lyase, or CSE, and hydrogen sulfide, but not cystathionine beta-synthase, in lymphocytes, responded to blood pressure changes. Deleting CSE in CD4+ T cells exacerbated angiotensin II-induced hypertension by reducing circulatory and renal T regulatory numbers. Hydrogen sulfide from CSE self-hydrates, liver kinase 1, thereby activating the AMP kinase energy pathway to promote TReg differentiation and proliferation, which then attenuates the vascular and renal immune inflammation, and thus, prevents hypertension. Dr Greg Hundley: Carolyn, this sounds like a very thorough study. What are the clinical implications? Dr Carolyn Lam: Endogenous CSE hydrogen sulfide in lymphocytes may be both a potential biomarker of hypertension, or its complications, or hydrogen sulfide donor may be a therapeutic approach to lower hypertension. Dr Greg Hundley: Great, Carolyn. Well, my next paper comes from Professor Goo Taeg Oh from Ewha Women's University, and it really involves the world of inflammation. So Carolyn, as you know, macrophages produce many inflammation-associated molecules released by matrix metalloproteinases, such as adhesion molecules, as well as cytokines, which play a crucial role in atherosclerosis. In this paper, the authors investigated the relationship between Ninjurin-1, or nerve injury-induced protein 1, a novel MMP9 substrate expression, and atherosclerosis progression. Dr Carolyn Lam: Ninjurin-1? Interesting. So, what were the results? Dr Greg Hundley: Well, Carolyn, Ninj1 expression and atherosclerosis progression were assessed in atherosclerotic aortic tissue and serum samples from coronary artery disease patients and healthy controls, as well as athero-prone, apolipoprotein E-deficient, or APOE -/- wild type mice. Two important findings, Carolyn. First, the authors in vivo results conclusively showed a correlation between Ninj1 expression in aortic macrophages and the extent of human and mouse atherosclerotic lesions. Ninj1-deficient macrophages promoted pro-inflammatory gene expression by activating mitogene-activated protein kinase, or MAP kinase, and inhibiting the phosphoinositide 3-kinase signaling pathway. Whole-body and BM-specific Ninj1 deficiencies significantly increase monocyte recruitment and macrophage accumulation in atherosclerotic lesions through elevated macrophage-mediated inflammation. Now, in addition and secondly, macrophage Ninj1 was directly cleaved by MMP9 to generate a soluble form that exhibited anti-atherosclerotic effects, as assessed both in vitro and in vivo. Treatment with the sNinj1-mimetic peptides, ML56 and PN12, reduced proinflammatory gene expression in human and mouse classically activated macrophages, thereby attenuating monocyte transendothelial migration. Moreover, continuous administration of mPN12 alleviated atherosclerosis by inhibiting the enhanced monocyte recruitment and inflammation characteristics of the disorder in mice, regardless of the presence of Ninj1. So in summary, Carolyn, Ninj1 is a novel MMP9 substrate in macrophages, and sNinj1 is a secreted athero-protective protein that regulates macrophage inflammation and monocyte recruitment in atherosclerosis. Dr Carolyn Lam: Wow, Greg, that was incredibly summarized. Thank you. Let's go through what else there is in today's issue. In cardiology news, Bridget Kuhn talks about how the pandemic intensifies the push for home-based cardiac rehabilitation options. There's a white paper by Dr Ho and colleagues, including me, describing the diagnostic dilemma of HFpEF. There's a Research Letter by Dr Gill talking about the cardiometabolic trait sepsis and severe COVID-19, a Mendelian randomization investigation. There's also a Research Letter by Dr Wu on the atlas of exosomes microRNAs secreted from human iPSC-derived cardiac cell type. Dr Greg Hundley: Carolyn, this issue is just packed with articles, because I've got five more to tell our listeners about. First, it's a research letter from Professor G. Hovingh, entitled, Inclisiran Durably Lowers LDLC and PCSK9 Expression in Homozygous Familial Hypercholesterolemia, The ORION-2 Pilot Study. Next, there's an ECG challenge from Dr Jason Gilge relating to AV conduction during atrial flutter. Next, Dr Keith Churchwell has a nice piece related to the importance of those involved in cardiovascular care and participating in their civic duties, including voting. Next, Professor Karthikeyan has nice On My Mind related to overestimation of stroke risk and rheumatic mitral stenosis and the implications for oral anticoagulation. And finally, Carolyn, another research letter, from Dr Pieter van Paassen, entitled, Neutrophils and Contact Activation of Coagulation as Potential Drivers of COVID-19. Well, Carolyn, how about we get on to our feature discussion and review in older patients, which antiplatelet therapy may be safest? Dr Carolyn Lam: Let's go! Dr Greg Hundley: Well, listeners, now we're turning to our feature discussion, and today we'll talk about antiplatelet therapy. And then we have with us, Dr Karolina Szummer from Karolinska Institutet, and our own Associate Editor, Dr Manos Brilakis from the Minneapolis Heart Institute. Welcome to you both, and Karolina, let's start with you. Could you describe for us your hypothesis and some of the background information that led you to perform this study? Dr Karolina Szummer: Thank you so much for having me here and for sharing the ideas behind our study. Current recommendations recommend that we use high-potent antiplatelet agents for treating myocardial infarctions, and in particular, elderly patients are not included. So we decided to do an observational study to look at patients in our Swedish registries treated for myocardial infarctions who were 80 years and older. Dr Greg Hundley: Very nice. Can you tell us a little bit more about your study design? And also the study population? Dr Karolina Szummer: The startup populations are all patients who were admitted to an acute coronary care unit for treatment of myocardial infarctions, and they were all 80 years and older, and they were included from 2010 to 2017. So this encompasses the period during which treatment with ticagrelor was introduced. So we are comparing to ticagrelor versus clopidogrel for the outcomes during the year, following the myocardial infarction. Dr Greg Hundley: And how many patients did you enroll in the study? And what were your study results? Dr Karolina Szummer: We enrolled, in total, 14,000 patients, and these consisted of non-STEMI and of STEMI patients. The majority, about two thirds, were non-STEMI patients. We show, in this study, elderly patients have a lower risk of readmission for myocardial infarction or stroke, but they have a higher risk of having readmission for bleeding and death. So the risk-benefit ratio seems to be skewed towards having, probably, more harm with ticagrelor being more risky than clopidogrel in this study population of elderly. Dr Greg Hundley: And was this true for both men and for women? Dr Karolina Szummer: Yes. So this was true for both men and women. And we did a sensitivity analysis. We looked closer at those who are younger than 80 years old, and in this patient population, the results selected in the same way as for our cohort of elderly, they actually did have the same benefit with a low risk of MI, stroke, and death, and high risk of bleeding. But in the elderly, we noticed a signal towards harm with an increased risk of death. Dr Greg Hundley: It sounds like with ticagrelor, did we have a lower risk of death and a slightly lower risk of myocardial infarction and stroke, but a higher risk of bleeding? Was that the findings? Dr Karolina Szummer: So for the elderly, there was a high-risk of death and bleeding with ticagrelor compared to clopidogrel, but a lower risk of ischemic component of MI and stroke. Dr Greg Hundley: And then with those under 80, those were the ones that had the lower risk of death, lower risk of MI and stroke, but the higher risk of bleeding? Dr Karolina Szummer: Yes, that's correct. So really the end point that differs most is that there is sustainment towards higher mortality in the elderly, because in both younger and elderly, the risk of readmission for bleeding was elevated in both. Dr Greg Hundley: Now, let's turn to our own Associate Editor, Manos Brilakis. Manos, can you help us put these results into perspective, relative to other studies that evaluate the efficacy of antiplatelet therapy, post myocardial infarction? Dr Emmanouil (Manos) Brilakis: I would like to start by congratulating Dr Szummer. It's a wonderful paper, and, I think, provide some new insights on how to use the medications in the ACS patients. And going on the background, if we look at the guidelines, both the European guidelines, as well as the American guidelines, what they say is that both ticagrelor, as well as prasugrel, are preferred and recommended for patients with ACS, both non-ST elevation ACS, as well as ST segment elevation myocardial infarction. And actually, European guidelines say that clopidogrel should only be used when prasugrel or ticagrelor are not available or are contraindicated. And this is based on two trials. One is the PLATO trial, and the other is the TRITON-TIMI 38, that both showed, actually, more benefit with the more intensive P2Y12 inhibitors. And this is what is extrapolated to all patient populations. But as you've heard before, there was only a minority of elderly patients that were included in those trials, about 13% to 15%, and that is why the present study is important, because it suggests that maybe we should look more carefully into the patient's age and potentially other characteristics like frailty or other comorbidities, that might actually alter the risk-benefit ratio. And maybe those medications should not be routinely given to all patients, but perhaps, elderly patients, or at least some of them, might not require, and actually be better off with clopidogrel. Dr Greg Hundley: Let's turn back to Karolina. Karolina, the study was observational. What do you see as, perhaps, a next study to follow up the results that you've brought to us with this study? Dr Karolina Szummer: So the next step would definitely be to do a randomized control trial in the elderly to explore this topic further, to really know for sure what the safety and efficacy is, and what's the best treatment would be for these patients. Dr Greg Hundley: Very good. And Manos, do you have anything to add? Dr Emmanouil (Manos) Brilakis: One more thing. So, there was actually a trial that compared ticagrelor as well as prasugrel with clopidogrel in elderly patients that was called the POPUlar AGE trial that was published last year. And actually this one, published earlier this year, and actually this trial randomized a thousand patients who were more than 70 years old, to either more-intensive or less-intensive. And the results were actually very similar to the findings from Dr Szummer's study from SWEDEHEART, showing that there was more bleeding without any ischemic benefit. And didn't show actually higher mortality but didn't show any significant benefit. So that actually adds to the data that maybe the elderly patients, the selection of antiplatelet agent should be taken into account. And I think for me, this also extrapolates the high bleed risk, higher risk of bleeding, based on criteria, which we currently use mainly for duration. We say, for example, if you're precise DAPT score, which is a score for determining risk of bleeding, is high, you should consider shorter duration of DAPT, but it doesn't say anything about the type of DAPT. And for me, this makes sense that the high bleeding risk, and age is one of the main risk factors for high bleeding risk, should be taken into account also for determining the type of P2Y12 inhibitor. Dr Greg Hundley: Well listeners, we've had a great discussion with Karolina Szummer from Karolinska Institutet, and our own Manos Brilakis from the Minneapolis Heart Institute, really reviewing the utility of ticagrelor versus clopidogrel in older individuals, above the age of 80, that have sustained myocardial infarction, and identifying that ticagrelor is associated with a higher risk of death and bleeding, as opposed to clopidogrel, opening the question up as to whether further studies in older individuals need to be performed to examine the efficacy of antiplatelet therapy. So, on behalf of Carolyn and myself, we wish you a great week and look forward to catching you On the Run next week. This program is copyright the American Heart Association, 2020.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.08.288605v1?rss=1 Authors: Huynh, T. D., Ashraf, O., Craig, H., Larmeu, L., Barker, B., Stepheson, C., Murcia, D., Howard, B., Sun, H. Abstract: Increasing evidence supports the idea that the CA1 of the hippocampus plays an important role in the pathogenesis of temporal lobe epilepsy (TLE). There is however a lack of proof that the over-excitation of CA1 alone is sufficient in inducing seizures in vivo. Furthermore, the relevance of the seizures induced from the over-excitation of CA1 to the pathophysiology of TLE is undetermined. Here, we employed optogenetics to activate pyramidal neurons (PNs) in CA1, which reliably induced generalized seizures in freely moving non-epileptic mice. We showed that repeated photostimulations had a kindling effect. In addition, seizures induced by over-active CA1 PNs were dominated by two distinctive onset patterns, i.e. hypersynchronous (HYP) and low voltage fast (LVF) activities, which are widely recorded in patients with and animal models of TLE. In our study, HYP seizures were predominantly associated with the first photostimulation and were entirely replaced by the LVF type afterwards. This phenomenon suggests that the activation of CA1 PNs, when occurring after the first seizure, could lead to the recruitment of GABAergic interneurons to participate in the seizure generation. These findings suggest that seizures induced from the over-excitation of CA1 PNs likely involved the same hippocampal networks and cellular mechanisms underlying TLE. Copy rights belong to original authors. Visit the link for more info

In this episode, Dr. Susan Dent, a breast cancer oncologist at the Duke Cancer Institute and Co-Director of the Duke Cardio-Oncology Program, discusses how to optimize cardiovascular health in patients with cancer and survivors as well as strategies to mitigate cardiovascular toxicity during and following completion of cancer treatment.   Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. Joining me today is Dr. Susan Dent, a medical oncologist at the Duke Cancer Institute and co-director of the Duke Cardio-Oncology Program. Dr. Dent will discuss how to optimize the cardiovascular health of patients with cancer and survivors. Her research on this topic will be presented during the ASCO20 Virtual Education Program. Dr. Dent receives grant funding from Novartis.  Full disclosures can be found on our episode pages.   Dr. Dent, welcome to the ASCO Daily News podcast.   Dr. Susan Dent: Thank you.   ASCO Daily News: Dr. Dent, there are 16 million cancer survivors in the United States. And as the survivorship population continues to grow, the association between cancer treatments and the development of serious cardiovascular complications has become more evident. Can you tell us more about this?   Dr. Susan Dent: Thank you. Yes, you're right. We are certainly seeing more survivors of cancer, which is very encouraging. However, as a consequence of that, we are now seeing more cancer survivors either develop cardiovascular disease or present with an exacerbation of preexisting cardiovascular disease. And the question is, why are we noticing that now?   I think as oncologists, we used to focus solely on the treatment of an individual's cancer and trying to cure that cancer and promote for survivorship. But what is clear now is that as individuals come to us for treatment of their cancer, they have preexisting cardiovascular risk factors. We know our population is aging. They come to us with preexisting hypertension, diabetes, or maybe even cardiovascular disease. We then treat them with cancer therapy that may exacerbate that or contribute to that. And then as they survive longer, we're seeing the cardiovascular consequences of preexisting risk factors in combination with cancer therapy that may promote the emergence of the cardiovascular disease.   So it's not as simple as just seeing a cancer patient and giving them cancer therapy anymore. We have to consider that cancer therapy in the context of the individual that we're treating and their preexisting cardiovascular risk factors to try and really prevent long-term cardiovascular disease. So while we're curing them of their cancer, we also want to try and make sure we promote good cardiovascular survivorship and cardiovascular health.   ASCO Daily News: Can you tell us about the patient populations that are presenting with more serious cardiovascular complications? Are breast cancer patients more likely to develop cardiovascular problems than patients with other cancers?   Dr. Susan Dent: That's a very good question. I think that a lot of the attention has been on the breast cancer population because we know that this is a population that's been exposed to anthracyclines in the past. We've used anthracycline sort of as a backbone of many of our therapies and then subsequently with the introduction of HER2 targeted therapies. So there was a lot of focus on this population, and that's where a lot of the research is looking at the risk of developing cardiovascular complications.   But it's not specifically the cancer per se. It is what we're treating those individuals with. So, for instance, if it's someone with renal cell carcinoma who is given tyrosine kinase inhibitor, that could lead to hypertension. And if they have preexisting hypertension, perhaps now it's exacerbated by the drug that we give them.   So the cancer is important in the context of the cancer therapy that we are offering them. And what we've learned over the last decade is that there are many cancer therapies that we offer our patients that can have cardiovascular consequences, not just on the heart. We think of the heart and heart failure. But sort of modern cancer therapies can lead to increased risk of hypertension, increased risk of arrhythmias, increased risk of prolong QTC, which is sort of a big issue right now, and in rare cases with immunotherapy, for instance, rarely myocarditis.   And so the cancer therapy that we deliver impacts the whole cardiovascular system, not just the heart, which is sort of where many of us think about heart and heart failure. So it's complex. And so we have to think about that whole individual. What are they coming into the cancer treatment with? What are their preexisting cardiovascular risk factors? What are we going to be giving them in terms of their cancer therapy, including radiation? And putting those together, what are the potential complications from that combination for that individual and their cancer?   ASCO Daily News: Right. It is very complex, indeed. So what is your recommended approach for monitoring cancer survivors and reducing their cardiovascular risk?   Dr. Susan Dent: I think it really starts at the beginning when we see these patients in our clinic and we start thinking about what we're going to offer them for cancer therapy. So survivorship really starts from the beginning when we first see these individuals. And the most important thing I think we need to think of as oncologists is thinking about what their risk factors are upfront when we're considering their cancer therapy.   So if I have someone coming into my practice, a breast cancer patient, and they have already have preexisting diabetes and hypertension, and I'm going to offer them an anthracycline and maybe HER2 targeted therapy, I need to think about optimizing those cardiovascular risk factors before, or at least as we start, the cancer therapy, because if we don't, we may get into trouble either during their cancer therapy or certainly after their cancer therapy. So it really needs to start at the beginning.   I think as oncologists, what we often do is we give our cancer therapy, and then when patients develop cardiovascular issues or problems, we then sort of refer them or ask for help from our cardiology colleagues. However, this is a very, I would say, reactive approach. We have to be more proactive in thinking about these things upfront.   You know we've now seen, for instance, with breast cancer survivorship improving, we're now seeing that those patients route seven, eight, nine years from the breast cancer diagnosis, more women are dying of cardiovascular disease than recurrence of their breast cancer. And I think as a breast cancer oncologist, that was a real eye opening study for me to see is that we're doing great in terms of the cancer survivorship, but we don't want to cure their cancer only to have them die of cardiovascular disease a couple years down the road.   ASCO Daily News: So what are the proactive steps that should be taken then so that a breast cancer patient, for example, has that attention that is required by the oncologist at the start, at the beginning of her cancer treatment if she has hypertension - addressing that issue at that point while she's getting her chemotherapy, so that she is not one of those tragic cases seven years post-treatment who has serious cardiovascular problems and potentially a fatality?   Dr. Susan Dent: That's a very good question. I think that, first of all, as oncologists, we need to be more aware or just to think about assessing patients as they come into their treatment. And I would have to say I don't think we're quite there yet. I don't think as oncologists that we're actually thinking about assessing cardiovascular risk factors when we start cancer treatments. So the first thing is to think about it.   The second thing is that we then have to start thinking about how we can look at assessing the risk factors. So there's a very sort of simple ABCDE approach to this that Dr. Michael Fradley will be speaking about in our educational session. A stands for just awareness of some of the cardiovascular risk factors. B, blood pressure monitoring, we know that hypertension is a big issue for almost half the US population. C stands for coronary artery disease screening. And D stands for diabetes control, healthy dietary choices, an E for exercise. And you'll hear more about this in our session, but just thinking about these things.   So how can we, as oncologists, even drill that down more? I can tell you what we're doing here at Duke is that we are trying to set up a screening process for all of our patients, starting out with the breast cancer population to begin with, so that we are building in our electronic health record-- we use Epic at Duke-- a screening process before patients start their treatment to try and identify those patients who might be at high risk of experiencing complications based on their history of risk factors, including, for instance, their BMI, body mass index, smoking history, diabetes, and so on.   And if those patients are deemed to be at high risk, we are trying to bring them into see a cardiologist with some interest in this area, cardio-oncologists to see if we can optimize any risk factors as they're starting their cancer treatment. I think this is the way that we have to move towards more proactive approaches, rather than waiting until these individuals run into problems with their uncontrolled hypertension or uncontrolled diabetes, because we certainly know that when they're on their cancer therapy, these things can occur. So this is a real shift I think for oncologists to try and consider of this approach. But I think it really is where we need to go.   There's also some research going on in the area of primary prevention. In other words, if there is an individual that you think might be at risk or if they're undergoing cancer therapy, that might place them at higher risk. There have been a number of studies looking at can we prevent them from developing cardiotoxicity based on cardiovascular medications that are out there?   ASCO Daily News: Well, there are a lot of interesting clinical trials underway in the cardio-oncology space right now. Can you tell us about some of these?   Dr. Susan Dent: My talk at the educational session will focus on some of the prevention trials. And most of the literature actually is on breast cancer. But there have been several trials that have looked at can we actually prevent cardiotoxicity or cardiovascular toxicity? These trials have essentially all been in the breast cancer population. They've been in patients who've been exposed to anthracyclines and in some cases HER2 targeted therapies, such as trastuzumab. And what they did is they randomized patients to receive cardio protective medications, such as an ACE inhibitor or a beta blocker or an ARB versus placebo. And they looked to see if they could prevent drops in the left ventricular ejection fraction, because as we know, this can occur with anthracyclines and HER2 targeted therapies.   Now, these studies, five of them in particular, three of those, three showed a positive benefit to giving these medications upfront versus two studies which showed no benefit. However, I have to say that how they measured benefit was as an attenuation in drop of LVF. And they were able to prevent a drop, but only in about three or four-- actually, I should say only about 3% to 4% prevention in drop. So in other words, if you had an LVF of 60%, it would prevent your ejection fraction dropping to 56%.   And so while that is encouraging, I would say, is it clinically meaningful? And so I think we need to do studies that include larger populations and populations at risk. Most of the individuals in these studies were healthy women in their mid 50s with very few cardiovascular risk factors. So moving forward, there is interest in trying to identify those patients at greater risk and then looking at the potential benefit from giving them cardiovascular medications upfront prior to starting their therapy.   ASCO Daily News: Are there any other trials that we should be keeping an eye on at the moment?   Dr. Susan Dent: There is another interesting study called UPBEAT. And what this study is it's looking at women with stage 1 to 3 breast cancer. And they are going to be looking at the cardiovascular health of these women, not only during the course of their therapy, but well into survivorship. So as women are starting the cancer therapy, they will undergo fitness testing. They will have cardiac MRI to look at their cardiovascular function. They will also be doing cognitive testing to look at the impact of cancer therapy on cognition. And these tests will reoccur throughout their treatment and then well into survivorship for several years.   And the reason why this is important is that we do not have any long-term data on the cardiovascular and cognitive effects of cancer therapy on patients. There's been a lot of literature in this space in the pediatric population where they've followed children for many years, but not in adult cancer survivors. So I'm really excited about this study. It's being done at a number of studies throughout the US. The PI is Dr. Greg Hundley. And we are certainly doing this study at Duke. And it will really provide some important insight into the long-term consequences of cancer therapy for patients.   ASCO Daily News: What role can exercise and diet modification play in improving the cardiovascular health of patients with cancer and survivors?   Dr. Susan Dent: We have always talked about exercise, but I don't think in the oncology world we've been as committed to it as we should. If you look at cardiovascular disease when individuals have a cardiovascular event, whether it be myocardial infarction or angina, they'll often be put into an exercise rehab program. We don't think about that after an individual goes through their cancer therapy. However, I think there is now clear evidence that exercise can be beneficial for our patients. In fact, it could be beneficial while they're going through their cancer therapy. And clearly, it can be beneficial into survivorship.   So the American Heart Association came out with a statement last year advocating for the benefit of exercise in our patient population. And subsequent to that, there are some ongoing studies looking at a combination of exercise and diet modification to try and deal with some of the risk factors, such as blood sugar control and hypertension. And I think all of these are actually combined when we look at overall risk. So I think that's a very exciting area is the whole field of exercise and I'll say exercise rehab for our patient population. I know at M.D. Anderson, for instance, many of their patients will be offered an exercise rehab program.   It also speaks to mental health I think as well in dealing with some of the fatigue that patients experience after they complete their cancer therapy. There's some also studies going on looking at drugs like statins, which we typically think of for the treatment of hypercholesterolemia. But certainly, these studies are looking at can statins actually benefit patients in preventing cardiovascular toxicity?   And finally, the other thing I'd like to say is that-- which we haven't touched upon-- is cardiovascular imaging. So there is research going on out there to try and determine what are the best cardiovascular cardiac imaging strategies that we can use to detect early evidence of cardiovascular toxicity. So Dr. Ana Barac is going to speak to that at our educational session. And she's going to discuss in what patients should we be using certain cardiovascular imaging techniques, such as echocardiograms, such as cardiac MRIs? When should we be using these? How should we be using these to either detect cardiovascular toxicity early? And can these techniques help us, I should say, even into survivorship? That along with cardiac biomarkers and how can they help us detect cardiotoxicity at an earlier stage?   So as you can see, there's lots going on in this space, not only from drugs that we can potentially prevent these toxicities, to exercise and lifestyle intervention, to cardiac imaging strategies, really looking at it from the very beginning prior to starting cancer therapy through their cancer therapy well into survivorship. Lots of opportunity to sort of look at different points where we can try and help individuals to really promote cardiovascular health.   ASCO Daily News: Excellent. I'd like to remind our listeners then that Dr. Dent's research on optimizing cardiovascular health in patients with cancer and survivors will be presented during the ASCO20 Virtual Education Program. And her article, "Optimizing Cardiovascular Health in Patients with Cancer, A Practical Review of Risk Assessment Monitoring and Prevention of Cancer Treatment Related Cardiovascular Toxicity," has been published in the ASCO Educational Book. Thank you, Dr. Dent for this insightful conversation today.   Dr. Susan Dent: Thank you.   ASCO Daily News: And thank you to our listeners for joining us for this episode of the ASCO Daily News podcast. Please take a moment to rate, review, and subscribe.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   COI Disclosure:  Dr. Susan Dent Honoraria: Novartis Canada Research Funding: Novartis US  

Welcome back to BTB, We Still Kicking off the new year. We got in this episode former LVF member, black business owner The Big Sweat The Big Dripper! We talk about fitness and creating his brand which leads us into football and it effecting us in the Game of Life. --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app

Agradece a este podcast tantas horas de entretenimiento y disfruta de episodios exclusivos como éste. ¡Apóyale en iVoox! Otra historia poco conocida, la Legion des Voluntaires Francais contre le Bolchevisme o lo que es lo mismo la LVF o Legión de Voluntarios Franceses. Una unidad de nacionalidad francesa, que apenas comenzada la Operación Barbarroja, se unieron a la Wehrmacht y combatieron en el frente ruso con sus camaradas alemanes. Su historia, batallas, ideales, etc.., en este programa Fuentes: Contra Stalin y De Gaulle, Carlos Caballero Jurado http://www.cheminsdememoire.gouv.fr/fr http://genealego.free.fr Música: Himno LVF Diversos audios de la formación de la LVF y de la LVF en el frente Espero que os guste y os animo a suscribiros, dar likes, y compartir en redes sociales y a seguirnos por facebook y/o twitter. Recordad que esta disponible la opción de Suscriptor Fan , donde podréis acceder a programas en exclusiva. Podéis opinar a través de ivoox, en twitter @Niebladeguerra1 y ver el material adicional a través de facebook https://www.facebook.com/sergio.murata.77 o por mail a niebladeguerraprograma@hotmail.com Telegram Si quieres acceder a él sigue este enlace https://t.me/niebladeguerra Además tenemos un grupo de convesación, donde otros compañeros, podcaster ,colaboradores y yo, tratamos temas diversos de historia, algún pequeño juego y lo que sea, siempre que sea serio y sin ofensas ni bobadas. Si te interesa entrar , a través del canal de Niebla de Guerra en Telegram, podrás acceder al grupo. También podrás a través de este enlace (O eso creo ) https://t.me/joinchat/Jw1FyBNQPOZtEKjgkh8vXg Escucha el episodio completo en la app de iVoox, o descubre todo el catálogo de iVoox Originals

Välkommen att lyssna till det sjuttonde avsnittet. Övervikt handlar om känslor !Varför har en del svårt att behålla sin vikt(nedgång) ? I detta avsnittet reflekterar jag om övervikt, bantning, arv & miljö, känslor, motivation och beteendeförändring "Man lever inte för att äta,man äter för att kunna leva..." Innehåll:Arv och MiljöÖvervikt handlar om känslorTröstätningBetydelsen av inre lugn och balans Bestående viktminskning Skillnad mellan Hunger och SugSockerberoendeMotivation - Drivkraft/energiOlika strategier för att förändra vår automatikSamt lite smått & gottMitt recept:Först - Bli medvetenFörst - Lär känna dig självFörst - Förstå ditt sinneFörst - Inre lugn & balansDärefter - beteendeförändringFlyktbeteende - våga möta livet och dig själv Om du även vill läsa texten, så finns en del av innehållet som en 8-sidig pdf-fil på min hemsida:www.amixe.se Mvh Lars

In this episode I cover acute left ventricular failure and pulmonary oedema.If you want to follow along with written notes on acute LVF and pulmonary oedema go to https://zerotofinals.com/medicine/cardiology/acutelvf/ or find the cardiology section in the Zero to Finals medicine book.This episode covers the pathophysiology of acute left ventricular failure and pulmonary oedema, the triggers, presentation, work up, investigations and management. It goes into further detail about the BNP blood test, echocardiogram and chest xray findings in heart failure.

Avsnitt 5 om Ekumenik - andra samtalet med Maria Klasson Sundin. Om receptiv ekumenik, om trygga rum och utbildningsbehov i hbtq+-kompetens. Maria är handläggare för ekumenik vid Kyrkokansliet i Uppsala och teologie doktor. Ska Svenska kyrkan driva processer i ekumeniska samtal och hur ska frågor om heteronormer tas upp? Hur påverkas Svenska kyrkan av ekumeniska samtal samt boktips till Frida och Erik. När LVF nämns menas Lutherska Världsförbundet. Detta är del 2 i dubbelavsnittet med Maria Claesson Sundin.

Call In! Horror comes to NYC from a jihadist that came over on a "diversity" visa.  Eight people are dead, and many are hurt.  After playing politics with the Vegas killings, the Democrats says we shouldn't play politics with this act. The LVF, which is a Democratic Super PAC, released a commercial showing a conservative running down kids in a pickup truck with a "don't tread on me" license plate and a confederate flag.    They pulled the ad down, but we still got it.      ISIS and Berekely Antifa met to discuss tactics in Europe.  These guys work with NAMBLA and now ISIS.  God, I hate them! We will recap of what is not going to happen on November 4th. Sign up to be a Patreon! http://www.patreon.com/patriot news www.patreon.com/patriotnews

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's issue features two exciting papers regarding heart failure in patients with breast cancer. We will be discussing this right after these summaries.                                                 Are we any closer to improving survival in Eisenmenger syndrome? Well, today's first original paper looks at contemporary trends and presents a multivariable mortality risk stratification model based on five simple noninvasive predictors of death in this population. Dr. Kempny and colleagues from Royal Brompton Hospital in London in the United Kingdom preform a large multicenter study in 1098 patients with Eisenmenger syndrome followed up between years 2000 and 2015.                                                 At the end of the study almost two-thirds of patients were on advance therapy for pulmonary arterial hypertension, while only six patients underwent lung or heart and lung transplantation. The study showed that despite advances in management, there was significant mortality amongst contemporary adults with Eisenmenger syndrome and 25.3% of patients died over a median follow up period of 3.1 years. Mortality was higher in older patients, those with a pre-tricuspid shunt, lower oxygen saturation, absence of sinus rhythm, or with a pericardial effusion.                                                 This important study is accompanied by an editorial by Drs. Lange, from Texas Tech University Health Sciences Center El Paso and Dr. Brickner from UT Southwest Medical Center in Dallas, Texas. The editorialists call for a prospective randomized control trials of the effect of current, or future pulmonary vasoactive disease targeting therapies on mortality in Eisenmenger syndrome patients, and say it's time to direct our efforts from improving risk-stratification towards improving survival.                                                 The next study provides experimental evidence of tolerogenic dendritic cell therapy as a novel anti-remodeling therapy in myocardial infarction. Tolerogenic dendritic cells are promising, potent, beneficial regulators of the post-infarct healing process via their control of T-regulatory cells and M1 M2 macrophages. Plus they have the advantage of the ease of administration and feasibility of a heart specific tolero-dendritic cell production.                                                 In the current paper by co-first authors, Drs. Choo and Lee, and co-corresponding authors, Drs. Chang and Lim, from Catholic University Korea and Chai University in Korea, authors generated tolerogenic dendritic cells by treating bone marrow-derived dendritic cells with TNF-alpha and cardiac lysate from mice with myocardial infarction. They then injected myocardial infarction mice twice with tolerogenic dendritic cells within 24 hours and at 7 days after LAD ligation. In treated animals, in vivo cardiac magnetic resonance imaging and ex vivo histology confirm the beneficial effects on post-infarct LV remodeling. Furthermore, subcutaneously administered tolerogenic dendritic cells near the inguinal lymph node migrated to the regional lymph nodes and induced infarct tissue specific T-regulatory T-cell populations in the inguinal and mediastinal lymph nodes, spleen, and infarcted myocardium, all of which elicited an inflammatory to reparative macrophage shift. The altered immune environment in the infarcted heart resulted in better wound remodeling, preserved left ventricular systolic function, and an improved survival following myocardial infarction. Thus, this study shows that tolerogenic dendritic cell therapy in a preclinical model of myocardial infarction may be potentially translatable into an anti-remodeling therapy for ischemic repair.                                                 The final paper reports results of cell therapy on exercise performance and limb perfusion in peripheral artery disease from the PACE trial, which is an NHLBI-sponsored randomized double-blind placebo-controlled phase two clinical trial, designed to assess the safety and efficacy of autologous bone marrow-derived aldehyde dehydrogenase bright cells in peripheral artery disease, and to explore associated claudication physiological mechanisms. In this paper from corresponding author Dr. Moye from UT School of Public Health in Houston, Texas and colleagues of the Cardiovascular Cell Therapy Research Network, a total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at nine sites to receive alcohol dehydrogenase bright cells or placebo. All patients underwent bone marrow aspiration and isolation of aldehyde dehydrogenase bright cells followed by 10 injections into the thigh and calf of the index leg. Results showed that there were no significant differences in the change over six months between study groups for the co-primary endpoint of peak walking time, collateral count, peak hyperemic popliteal flow, and capillary profusion measured by magnetic resonance imaging.                                                 Additionally, there were no significant differences for the secondary endpoints including quality of life measures. There were no adverse safety outcomes. Interestingly, a post-hoc exploratory analysis suggested that aldehyde dehydrogenase bright cell administration might be associated with an increase in the number of collateral arteries in participants with completely occluded femoral arteries.                                                 In summary, cell therapy did not improve peak walk time or magnetic resonance outcomes, and the changes in peak walk time were not associated with the anatomic or physiologic MRI endpoints. However, future peripheral artery disease cell therapy trial design may be informed by new anatomic and perfusion insights. These and other issues are discussed in an accompanying editorial by Drs. Breton-Romero and Hamburg from Boston University School of Medicine. Well, that wraps it up for our summaries, now for our feature discussion.                                                 We are really in the grove here in Washington, D.C. and I am borrowing the words of my very special, star associate editor, guest, Dr. Gregory Hundley, and he's from Wakefield University School of Medicine. We're discussing two very important papers and they deal with the risk of heart failure following breast cancer. Why they're so important? Well, first of all, it's about time we looked at this problem in detail, and secondly, they actually represent papers in a new section of the journal called "Bridging Disciplines," and in this case cardio-oncology. Very, very important topics.                                                 We're here with the corresponding authors of both papers, Bonnie Ky from University of Pennsylvania School of Medicine and Dr. Margaret Redfield from Mayo Clinic. Dr Gregory Hundley:      Thank you, Carolyn. I really appreciate that wonderful introduction and also the chance to talk with Bonnie about this exciting topic.                                                 So, Bonnie, you've got a paper here, now, where you did a study in patients with breast cancer, and it sounds like you acquired echocardiograms over a period of time. Can you tell us a little bit about that? Dr Bonnie Ky:                     Correct. So this is longitudinal prospective cohort study, it's an NIH-funded R01, whereby we are enrolling patients from the breast cancer clinic who are receiving doxorubicin or trastuzumab or a combination of the two therapies. And we're performing very careful cardiovascular phenotyping, from the time at which they initiate chemotherapy through their chemotherapy and then annually once a year we have them come back, for a total follow up time of 10 years.                                                 We took a subcohort, 277 patients, and from their echocardiograms, we analyze them very carefully for various measures of left ventricular size, function, not only systolic function but also diastolic function. We also looked at measures of contractility such as strain in multiple dimensions, and then also measures of ventricular arterial coupling, as well as arterial loads, so how the ventricle interacts with the arterial system. And what we found was that over a 3.2 period time period, on population average, these modest declines in left ventricular ejection fraction, and even across all three treatment groups, and even at three years there were persistent LVF declines. Dr Gregory Hundley:      So, I understand, Bonnie, that you also collected some information as to whether or not these patients were experiencing symptoms associated with heart failure. How did the imaging markers relate to the symptomatology associated with heart failure? Dr Bonnie Ky:                     What we found was that early changes in arterial stiffness or total arterial load, as well as early changes in EF were associated with worse heart failure symptoms at one year. A lot of our other analysis was focused on defining what echo parameters of remodeling, size, function are driving or associated most strongly with LVF decline, as well as LVF recovery. Dr Gregory Hundley:      And then at two years, what happened? Did the echo parameters, were they still associated with heart failure or was there a little discrepancy there? Dr Bonnie Ky:                     Interestingly, at two years ... no, there was no significant association with changes in arterial load and heart failure symptoms at two years. Dr Gregory Hundley:      So there might be something transient that's occurring that is associated with heart failure early, and then the patients still had heart failure late, so maybe something else is operative. What do you think we need to do next? What's the next step in your research and then other investigators around the world; what do we need to do to design studies to look at these issues further? Dr Bonnie Ky:                     Yeah. What does the field need, the field of cardio-oncology that's really growing and developing at rapid paces. Some of the major findings from the study was that changes in total arterial load were very strongly associated with both LVF decline and LVF recovery. So total arterial load is the measure of blood pressure or total arterial stiffness, it's derived from blood pressure. And to me, that begs the question, or begs the next step is that changes in blood pressure are associated with decline as well as recovery. I think, oh, as cardiologists we've also always recognized the importance of afterload reduction. And to me, this study suggests that we need a study, a randomized clinical trial, looking at blood pressure lowering in this population to help mitigate LVF declines. Dr Carolyn Lam:                I'd actually like to turn it back to you. You are world-renowned for your work in cardio-oncology. Where do you think this fits in, and where do you think we need to address most urgently? Dr Gregory Hundley:      I think where this fits in wonderfully is a lot of individuals around the world are collecting echocardiographic measures, and all different types. And what Bonnie has helped do is clarify what we would expect to see in this particular patient population. How those measures change over time and that feeds into another block of data, when the measurements head south, do we change therapy, do we add protective agents, and things of that nature. So I think Bonnie's work really contributes on that front. What she has also pointed out is that more research needs to be performed, not necessarily because the patients had heart failure symptomatology at two years, but not necessarily associated with the decline in EF; are there other systems in the cardiovascular realm that are being affected? The vascular system- Dr Carolyn Lam:                Yeah. Dr Gregory Hundley:      Skeletal muscle, many other areas. So as cardiologists start to work more with oncologists in this space, and we're all working together to make sure that not only patients survive their cancer, but they have an excellent quality of life, I think we'll see, as we have in other heart failure syndromes, a look toward other aspects of the cardiovascular system, body in general, to reduce the overall morbidity associated with the disease.                                                 I think what we need to recognize as cardiovascular medicine specialists is that now for many forms of cancer, cardiovascular events, and certainly morbidity are becoming the primary issue that folks have to deal with with survivors. It's not necessarily the cancer recurrence, it's not necessarily a new cancer, it's cardiovascular. So we've got to integrate cardiology earlier in working with oncologists to improve overall survival and create an excellent quality of life from our different perspectives. Dr Carolyn Lam:                So, Maggie, let's move on to your paper now. You looked at radiotherapy's effect, whereas Bonnie looked at chemotherapy's effect. Could you tell us what you did and what you found? Dr Margaret Redfield:    The rationale for doing this study was, of course, seeing a lot of patients with HFpEF who had had radiation therapy for breast cancer, and I always just sort of assumed that that was because 12% of women over the age of 40 get breast cancer and 20% of women over the age of 40 get heart failure, but it seemed to be somehow more common than that. The other rationale was that radiation therapy does not actually affect the cardiomyocytes; they are very radiation resistant. And what radiation does is cause microvascular endothelial cells damage and inflammation, and that is felt to be fundamental in the pathophysiology for HFpEF.                                                 So we thought we should look at this. I collaborated with a radiation oncologist and oncologists, and they were interested in looking at this because there's a lot of techniques now to reduce cardiac radiation exposure during radiation therapy, including proton beam therapy, and they're trying to prioritize who they use this new technology on. So what we did was start with a population-based study, all women who lived in Olmsted county who received radiation therapy for breast cancer in the contemporary era, where they're already using these dose reducing techniques. So we wanted to make it relevant to what's going on today. And so we started with a base cohort of all women. We matched patients' cases, it was a case-control study, so we matched cases and controls according to their age at the time of breast cancer, whether they had heart failure risk factors, like hypertension or diabetes, whether they got adjuvant chemotherapy, and tumor size, because we felt it was important that radiation could affect different parts of the heart, depending on whether it was right- or left-sided tumor.                                                 And what we found is that the risk of heart failure increased with the mean cardiac radiation dose. We measured the mean cardiac radiation dose in every case and every control from their CT scans and their radiation plants. And as the radiation dose went up, the risk of heart failure went up, even matching or controlling for chemotherapy, which wasn't used that often in this group, or heart failure risk factors. And the vast majority of these cases were indeed HFpEF.                                                 So we then looked at factors that happened in-between the radiotherapy and the onset of heart failure, making sure that this all wasn't just coronary artery disease, 'cause we know radiation can increase the risk of coronary artery disease. And indeed there were, only in about 18% of cases was there a new episode of coronary disease in the interim between the radiotherapy and the breast cancer. So, basically found that the mean cardiac radiation dose, even in today's era, does increase the risk of heart failure with preserved ejection fractions. Dr Carolyn Lam:                The things that stuck out to me ... it's population based. You did such a comprehensive study to really answer very key questions: dose of radiation, is it really just mediated by age and age-related risk factors, is it just about MI or could it be more microvascular disease? Congratulations, I really appreciated this paper. Some of the take-home messages are directly related to the treatment of breast cancer, isn't it? And about the importance of minimizing radiation dose if possible. I suppose one of the take-homes is, as well, for screening and watching out for heart failure. One thing though: how were these woman diagnosed with HEpEF? I mean, this is always the questions I get. How do you get diagnosed with HEpEF? Dr Margaret Redfield:    Right, well, first we started with looking to see if they had a ICD code for heart failure, and then we looked at each case of heart failure and determined if they either met Framingham criteria at the time of the diagnosis and the majority of them did. If they didn't actually meet the Framingham criteria, we looked to be sure there was a physician diagnosis of heart failure in the record and that they had supportive evidence of heart failure: echocardiographic findings, natriuretic peptide findings, and other clinical characteristics of heart failure.                                                 And importantly, in the large control group from where we, you know, got our controls, people, a very large group of patients who did not get heart failure, we'd use natural language processing to look at all those records to make sure we weren't missing anybody who didn't have an ICD diagnosis or code for heart failure to make sure we weren't missing any cases of heart failure. So, we really tried to use very stringent methods to make sure we had true cases and control groups. Dr Carolyn Lam:                Indeed, and it actually goes back to Bonnie's paper as well, where we have to remind everyone that the diagnosis of HEpEF really starts with the symptomatology of heart failure in particular, that you so rigorously determined. I think just one last thing, Maggie: what do you think this implies now, for HEpEF? What do we do in general so the non-radiation-associated, do we believe more the Walter Paulus-Carsten Tschope hypothesis, and if so, what do we do? Dr Margaret Redfield:    Yes, well I think it really does support that hypothesis. We know that radiation therapy, again, we know what it does to the coronary microvascular endothelial cells and that's been elegantly worked out both in patients and in animal models. I think this really supports the Paulus hypothesis because this microvascular damage was able to produce heart failure, so I think that really supports that hypothesis. And there's been some studies showing decreased coronary flow reserve in HEpEF patients; it's very common. So I think indeed it does support that hypothesis and that the coronary microvasculature is key in the pathophysiology of HEpEF.                                                 However it's a little scary to me because that sort of damage, once it's established, may be very hard to treat. You know, proangiogenic strategies in peripheral vascular disease have not yet yielded the benefits that we hoped for, so I think it's a tough therapeutic challenge that'll be very important to try to address in pre-clinical studies to try and figure out once the microvasculature is so damaged how do we treat that? How do we reverse that process? Dr Carolyn Lam:                Yeah. Words of wisdom. Maggie, thanks so much for inspiring, just all of us in this field. I just had to say that. You know, you are the reason that I am totally in love with HEpEF. (laughter) Dr Margaret Redfield:    (laughter) Dr Carolyn Lam:                So thank you so much for joining me today on the show. In fact, thank you to all my three guests.                                                 You've been listening to Circulation on the Run. You must tell everyone about this episode, it is full of gems.                                                 Thank you, and tune in next week.  

Det är högsommar och det stora biofilmerna sköljer över oss. Vi känner oss helgalna ute i öknen där en stor lastbil fraktas med supermodellskonkubiner till okänd ort. Vi köper Vip-pass med extra allt till djurparken som får Kolmården att blekna. Tyvärr så är det sista dagen parken är öppen för djuren springer, flyger och härjar fritt inne i parken.Vi måste dessutom rädda världen från undergång igen. Tillbaka till 1984 för att beskydda mamman som kommer bli attackerad av en galen robot. Men hon kan tydligen numera klara sig självFölj med oss ifall ni inte vill dö.... Eller om ni vill höra oss bli uppspelta, upprörda, och imponerade över Mad Max : Fury Road, Jurrasic World och Terminator : Genisys.

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In this podcast, the ARZone team are joined by Robin Lane, co-founder with Alison Lane of the London Vegan Festival (LVF). Robin, an ethical vegan since 1982, talks about the development of the LVF, vegan education, national animal advocacy organisations, grassroots campaigns, and much more. You may also LISTEN HERE.