Podcasts about Titin

Can a sober celebrity build a booming booze brand? The hosts dig into the paradox behind a high-profile actress and entrepreneur who doesn't drink – but is betting big on alcohol. Plus, a tea company rooted in a 1930s family recipe is brewing something fresh with younger consumers. With a grassroots strategy and nostalgic appeal, could it be the next big thing for Gen Z and millennials? Show notes: 0:35: Live & Not In Person. Coffee Shots. Irony Vs. Authenticity. A $30M Joyride. Evil Does Good, Again. – Was BevNET Live Summer 2025 an amazing event? The hosts can't be sure at this point. Wellness shot maker Sol-ti gets a big time partner in a deal that surprised some of the Taste Radio team. Ray goes on a classic rant about authenticity, but John tries to reel him in. Everyone is happy for BFY candy brand Joyride, as well as a new and healthier option for crunchy cheese snacks and an Indian food brand designed to create fast and convenient meals. 19:32: Kelley McShane, Owner, Granny Squibb's – Kelley discusses her journey into the beverage industry and her role in reviving and growing Granny Squibb's. She discusses the New England-based iced tea brand's mission-driven approach and how it emphasizes a grassroots growth strategy focused on the region before national expansion. Kelley also explains how the brand's nostalgic packaging and premium ingredients help it stand out and her commitment to building a sustainable, socially impactful beverage company. 33:23: Interview: Daniel Danes, Founder & CEO, TITIN – Originally from Madrid and inspired by his great-grandmother "Titin," Daniel talks about his goal of bringing high-quality, traceable olive oil to the U.S. He discussed Titin's distinctive purple squeeze bottle and how he's attempting to build trust with younger consumers via transparency and taste, while keeping prices competitive. Daniel also highlights TITIN's recent market launch in New England and why he believes the U.S. offers greater business potential than Spain. Brands in this episode: Singing Pastures, Monsoon Kitchens, Granny Squibb's, Titin, Farmer Foodie, Fancypants Baking Co., Joyride, Starbucks, Sol-ti, Spindrift, Brew Dr., Koia, Vive Organic, Betty Buzz, Betty Booze, Delola, Lesser Evil, Jack Daniel's, Coca-Cola, Cheetos, Masala Gossip

Big ideas, bold flavors, and unfiltered insights—welcome to Austin, where the future of CPG is being written in real time. At Taste Radio's Austin Meetup, we sat down with trailblazers and trendsetters redefining how brands are built and scaled. From Better Sour co-founder Bella Hughes to Torchy's Tacos founder Mike Rypka and Snaxshot's Andrea Hernández, these conversations explore what it really takes to innovate, connect with consumers, and lead with authenticity in a rapidly evolving industry. Show notes: 0:45: Buyers As Far As The Eye Can See. NNE FTW. Boiler Room. Caffeine, Protein & Pole-Caught Tuna. With BevNET Live just two weeks away, excitement is building as Casey's joins a strong lineup of participating retailers, including Stop & Shop, Whole Foods Market, Circle K, H-E-B, The Goods Mart, and Top Ten Liquors. John and Ray recap the recent Naturally New England Naturally Rising event, which spotlighted standout emerging brands, including Singing Pastures and Farmer Foodie. Mike and John revisit their tour of Athletic Brewing's HQ in Milford, CT, before the hosts riffed on consumer interest in dual-functionality products and a canned tuna brand grounded in sourcing transparency. 19:23: Interviews from Taste Radio's Austin Meetup – Mike Rypka, the visionary founder of Torchy's Tacos, shared his journey from launching a food trailer to building a nationally recognized franchise. Steven Santangelo of Matriarch Wealth Management discussed how his firm helps CPG founders navigate the complexities of financial planning, particularly during critical growth and exit stages. Bella Hughes, co-founder of Better Sour, reflected on building a culturally inspired candy brand and the challenges of innovation in a legacy category. Andrea Hernández, the sharp mind behind Snaxshot, delivered an unfiltered perspective on food and beverage trends, highlighting the importance of authenticity and emotional resonance in brand storytelling. And Michelle Breyer, CMO of the Texas-based accelerator SKU, shed light on how the organization nurtures early-stage consumer brands, emphasizing the pivotal role of founder mindset and market fit in driving long-term success. Brands in this episode: Better Sour, Torchy's Tacos, Farmer Foodie, Monsoon Kitchens, Inc., Granny Squibb's, TITIN, Fancypants Baking Co., Singing Pastures, Athletic Brewing, Lucky Saint, 5-hour Energy, Ascent, Pole & Line, Fly By Jing, Siete, Wildwonder, Bachan's, Daily Crunch, Leisure Hydration, BodyArmor, Vitaminwater, NoBull

Rok Vilčnik (s psevdonimom rokgre) je izjemno vsestranski ustvarjalec; med drugim je pesnik, dramatik, scenarist, glasbenik, režiser in pisatelj. Pri založbi Litera je lani objavil svoj četrti roman Mehanizem. Roman je napisal kot alegorijo o izjemni volji po preživetju. Od tu naprej pa si sledijo presenečenja: za svoj obstoj si prizadevata mehanični bitji Titina in Titin; na hrbtu nosita škatlo z lučko; njuna svetloba vsaj nekoliko osvetljuje svet okoli njiju, svet neskončne teme. In ko začne nekega dne Titinina svetloba slabeti, se njuno potovanje, pustolovščina začne. Na svoji poti srečata zelo različna bitja, in pisatelj si je dal precej duška, predvsem pa mu je uspelo, da je zgodbo izpeljal občuteno in za žanr alegorije prepričljivo. Več o romanu pove Rok Vilčnik v Izšlo je, v pogovoru z Markom Goljo. Nikar ne zamudite.

Piše Muanis Sinanović, bere Igor Velše. Rok Vilčnik je eden najpomembnejših mariborskih besednih ustvarjalcev z raznolikim opusom. Prav posebno mesto v sodobni literarni produkciji na slovenskem ima njegov najnovejši roman Mehanizem. Gre za romaneskno pravljico, ki je primerna tako za otroke kot za odrasle. Vsebuje namreč zelo bogato alegorično vsebino, podano prek razvejanega domišljijskega sveta. Zgodba govori o dveh igračah, Titini in Titinu, ki se prebudita v škatli. Titinin ključ za navijanje je zlomljen, zato morata čimprej poiskati nekoga, ki ga bo popravil. Znajdeta se v svetu teme, ki ga upravlja Mož brez sence, pomaga pa mu vojska rogačev. Pripoved ima klasično strukturo pustolovščine. Kratka poglavja gradijo intenzivne dogodivščine s tipičnimi nenadnimi obrati. Na formalni ravni Vilčnikovo delo sledi preizkušenim obrtniškim prijemom. Jezik je jasen in discipliniran. V tem pogledu pripoved spominja na najuspešnejše ameriške animirane filme. Naslednja asociacija so umetniške videoigre neodvisnih razvijalcev, ki svojim umetninam vdahnejo unikaten domišljijski pečat. Zdi se, da je vsako poglavje kot misija, ki nas vodi do končnega soočenja z nepredvidljivim obratom. Razvijalci gotovo ne bi zgrešili, če bi roman Mehanizem prevedli v obliko videoigre. Na notranji, vsebinski ravni, pa se Vilčnik, ki v delo gotovo vnaša tudi občutje lutkarskega sveta in lutkovnih iger, s katerimi ima prav tako izkušnje, dotika pravprašanj o izvoru pomena in sreče, razmerij med egoizmom in tovarištvom, ljubeznijo in sovraštvom ter tudi kozmologije. V sodobnem svetu ima akademsko etablirana književnost, predvsem romani, vlogo umeščanja individualiziranega subjekta v izgubljeno celoto in celostnost. Nasprotno pa skuša fantazijska književnost, ki sta jo etablirala univerzitetna kolega John Ronald Reuel Tolkien in Clive Staples Lewis, ustvarjati oziroma domišljijsko poustvarjati svetove, ki so celostni in zaceljeni, od katerih posameznik ni ločen, temveč je njihov organski del. Prav v tak svet sta umeščena in ga odkrivata Titina in Titin, pri tema pa segata tudi po metafiziki. Vendar ne gre za zapleteno filozofsko govorico, temveč za »filozofijo«, kakršno poznajo otroci, preden povsem ponotranjijo postulate sodobnega sveta. Ta svet je tudi umetno zarezal črto med odraslimi in otroki, ki implicira, da otroci živijo v fantazijah, odrasli pa dojemajo svet takšen, kakršen je. To je filozofsko gledano seveda naivna predpostavka, knjige, kot je Vilčnikova, ki nas znova postavijo v otroško perspektivo in jo povežejo z našim odraslim jazom, pa omogočajo, da to občutimo na najgloblji ravni. Dogodivščine in dileme Titnia in Titine so namreč podane iz neke, recimo, nepokvarjene perspektive, ki pa se še vedno nahaja v nas, le da smo jo prekrili s plastmi cinizma in obrambnih mehanizmov. S tega vidika nam lahko pravljice včasih dajo več kot romani, Vilčnikovo delo pa je skoraj idealen spoj obojega. Zgodba je zelo privlačna in bralca zlahka posrka. Obenem je polna zdravilne toplote in nežnosti, pri čemer se, kar je pomembno za kvaliteto dela, ne izogiba eksistencialni tesnobi ob soočanju s končnostjo in zlom. Pri tem pa ne gre v nasprotno skrajnost, kot je značilno za nekatere sodobne pristope k fantazijskemu pisanju, in se ne spušča v nikakršno eksploatacijo groze, seksualnosti, nasilja in podobno. Kot rečeno, roman je v celoti primeren za otroke. Vilčnik načeloma uspešno, vendar ne nujno povsem, vzpostavlja različne ravni resničnosti, ki spominjajo na predmoderne religiozne metafizike in neoplatonistično filozofijo. Mešajo se tudi časi, sanje in resničnost, praspomini in trenutni doživljaji. To prinaša delu dodatno, mestoma osupljivo dimenzijo, vendar so prehodi občasno morda preveč zapleteni ali prehitri, zgoščeni pa so v zaključku zgodbe, kar nekoliko otežuje dojemanje. Kljub temu pa je zaključek izjemno pomenljiv in to ne kvari končnega vtisa o tej skrivnostni knjigi, ki nas strese iz banalnega vsakdana, nas angažira in popelje v bujne nadrazumske svetove, ki jih ne bomo zlahka pozabili.

Programme de MICHEL TITIN-SCHNAIDER pour webSYNradio : Autobiophonie + Entropie passagère. J'ai eu l'idée de cette composition parce que j'ai constaté être très sensible à certains sons : notamment les hirondelles et la 40e de Mozart. En recherchant pourquoi, j'ai compris qu'il s'agissait de sons entendus très jeune. J'ai alors eu l'idée de construire une "autobiophonie". Le début est imaginaire bien sur car je ne me rappelle pas de ce que j'ai entendu avant ma naissance mais j'ai fait bonne place aux sons qui devaient m'entourer alors comme l'ORTF, Leon Zitrone, et Tino Rossi, la seule "musique" qu'auraient pu écouter mes parents. Entropie Passagère qui fait suite à cette autobiophonie est une pièce électronique que j'ai faite en 1979 (donc à 19 ans) avec un synthétiseur modulaire que je venais de me construire. Dès ce tout premier morceau il y avait les bases de beaucoup d'aspects de ma musique : la volonté de raconter une histoire, de proposer une interprétation métaphorique, de créer une ambiance angoissante, oppressante, le plaisir (musical!) du chaos, mais aussi le retour au calme, l'impermanence des choses."

Kebaktian 2 Minggu XIX Sesudah Pentakosta GKP Jemaat Bandung Minggu, 29 September 2024 pukul 09.30 WIB Tema : "Menjadi Garam = Berdamai Dengan Perbedaan" Bacaan Alkitab : Markus 9 : 38-50 Pelayan Firman : Pdt. Titin Meryati Gultom, S.Si., Th.M. @GKP Bandung September 2024

"Battle started in Titin city of Chin State, difficulty in transporting goods during monsoon season" Myanmar Nway Oo Chronicle 27th May 2024 (Moemaka Article).This item has files of the following types: Archive BitTorrent, Item Tile, Metadata, PNG, Spectrogram, VBR MP3

Kebaktian 2 Minggu Prapaskah VI (Minggu Palmarum) GKP Jemaat Bandung Minggu, 24 Maret 2024 pukul 09.30 WIB Tema : "Tuhan Memerlukannya" Bacaan Alkitab : Markus 11 : 1 - 11 Pelayan Firman : Pdt. Titin Meryati Gultom, Th.M. @GKP Bandung Maret 2024

Kebaktian 1 Minggu Prapaskah VI (Minggu Palmarum) GKP Jemaat Bandung Minggu, 24 Maret 2024 pukul 07.00 WIB Tema : "Tuhan Memerlukannya" Bacaan Alkitab : Markus 11 : 1 - 11 Pelayan Firman : Pdt. Titin Meryati Gultom, Th.M. @GKP Bandung Maret 2024

Héctor Alfonso Souza es profesor de música, especialista en bibliotecología, escritor y músico. En el programa #CiudadAbierta conversamos con el artista, quien nos habló sobre sus novelas cortas, “Beatriz” y “Detective Rebolledo” y además de su nuevo trabajo discográfico llamado “El Sueño de Avril”. Sus novelas están cargadas de hechos históricos, los que son intervenidos por personajes ficticios que circundan momentos relevantes de la historia y paisajes del puerto de Valparaíso de otras épocas, por otro lado, su obra musical es conceptual y con pinceladas de ciber punk, todo merodeado por el sonido del progresivo y la música de raíz latinoamericano, fuertemente influenciada por el neoprogresivo. La producción creativa de Titín, como se hace llamar Hecto Souza, está disponible y a muy buen precio en “Mar de Letras”, librería y disquería al costado de Cine Insomnia.

Kebaktian 1 Minggu Biasa XVI GKP Jemaat Bandung Minggu, 24 September 2023 pukul 07.00 WIB Tema : "Semua Orang Berharga Di Mata Allah" Bacaan Alkitab : Matius 20:1-16 Pelayan Firman : Pdt. Titin Meryati Gultom, Th.M. @GKP Bandung September 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.02.530843v1?rss=1 Authors: Huang, K., Ashraf, M., Rohani, L., Luo, Y., Sacayanan, A., Huang, H., Haegert, A., Volik, S., Sar, F., LeBihan, S., Liew, J., Roberts, J. D., Tibbits, G. F., Churko, J. M., Sanatani, S., Collins, C., Brunham, L. R., Laksman, Z. W. Abstract: Background: Protein truncating mutations in the titin gene are associated with increased risk of atrial fibrillation (AF). However, little is known regarding the underlying pathophysiology. Methods: We identified a heterozygous titin truncating variant in a patient with unexplained early-onset AF using whole exome sequencing. We used atrial and ventricular patient induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), CRISPR/Cas9 genetic correction, and engineered heart tissue (EHT) constructs to evaluate the impact of the titin truncating variant on electrophysiology, sarcomere structure, contractility, and gene expression. Results: We generated atrial and ventricular iPSC-CMs from the AF patient with the titin truncating variant and a CRISPR/Cas9 genome corrected isogenic control. We demonstrate that the titin truncating variant increases susceptibility to pacing-induced arrhythmia (prevalence of arrhythmogenic phenotypes, 85.7% versus 14.2%; P = 0.03), promotes sarcomere disorganization (mean {+/-} SEM, 66.3 {+/-} 6.8% versus 88.0 {+/-} 2.9%; P = 0.04) in atrial iPSC-CMs, and reduces contractile force (0.013 {+/-} 0.003 mN versus 0.027 {+/-} 0.004 mN; P less than 0.01) in atrial EHTs compared to isogenic controls. In ventricular iPSC-CMs, this variant led to altered electrophysiology (90.0% versus 33.3%; P = 0.02) and sarcomere organization (62.0 {+/-} 3.9% versus 82.9 {+/-} 2.9%; P less than 0.01) with no change in EHT contractility compared to isogenic controls. RNA-sequencing revealed an upregulation of cell adhesion and extracellular matrix genes in the presence of the titin truncating variant for both atrial and ventricular EHTs. Conclusions: In a patient with early-onset unexplained AF and normal ventricular function, iPSC-CMs with a titin truncating variant showed structural and electrophysiological abnormalities in both atrial and ventricular preparations, while only atrial EHTs demonstrated reduced contractility. Whole transcriptome sequencing showed upregulation of genes involved in cell-cell and cell-matrix interactions in both atrial and ventricular EHTs. Together, these findings suggest titin truncating variants promote the development of AF through remodeling of atrial cardiac tissue and provide insight into the chamber-specific effects of titin truncating variants. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Please join author Mohamed Abdel-Wahab and Associate Editor Stefan James as they discuss the article "Comparison of a Pure Plug-Based Versus a Primary Suture-Based Vascular Closure Device Strategy for Transfemoral Transcatheter Aortic Valve Replacement: The CHOICE-CLOSURE Randomized Clinical Trial." Dr. Carolyn Lam: Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, a very interesting topic, looking at closure devices at the sites of access for patients that are undergoing TAVR procedures. But before we get to that, how about if we grab a cup of coffee and start with some of the other articles in the issue. Would you like to go first? Dr. Carolyn Lam: I would love to and I would like to describe not just one, but two articles from recent SGLT2 inhibitor trials. So, the first paper is an analysis of the DAPA-HF trial. Now we know that circulating high sensitivity, cardiac troponin T predominantly reflects myocardial injury. And higher levels are associated with a higher risk of worsening heart failure and death in patients with heart failure with reduced ejection fraction or HFrEF. But what about the prognostic significance of changes in high sensitivity troponin T over time and the effects of Dapagliflozin and on clinical outcomes in relation to baseline levels, as well as the effect of dapagliflozin on the high sensitivity troponin T levels? Well, this is what this study answers. It's a biomarker substudy of the DAPA-HF trial from Dr. Berg of the TIMI study group at Brigham women's hospital and colleagues. Dr. Greg Hundley: Wow. Carolyn, very interesting. So remind us about the DAPA heart failure trial. What was it about? Dr. Carolyn Lam: Ah, well, DAPA-HF was a randomized double blind placebo control trial of dapagliflozin in patients with symptomatic HFrEF defined by injection fraction 40% or less wherein dapagliflozin significantly reduced the primary endpoint of cardiovascular death or worsening heart failure events. And in today's biomarker substudy increases in high sensitivity, cardiac troponin T over a one year interval of time were highly predictive of subsequent risk of worsening heart failure and cardiovascular death. The effect of dapagliflozin on the primary endpoint was consistent irrespective of baseline troponin T concentration with no evidence of attenuated treatment benefit in those with very high troponin T concentrations. Dr. Greg Hundley: Very interesting Carolyn. Now you've got another study. Is this one on EMPA? Dr. Carolyn Lam: You are right. Thank you. The next paper is and analysis of the Emperor-Preserved trial. As a reminder, Emperor-preserved study the SGLT2 inhibitor empagliflozin in patients with HFpEF this time, which is a left ventricular ejection fraction above 40, and showed a significant reduction in the risk of cardiovascular death or heart failure hospitalization. The current paper evaluated the efficacy of empagliflozin on health related quality of life in patients with HFpEF and whether the clinical benefit observed with empagliflozin varied according to baseline health status. Dr. Greg Hundley: Very nice, super review Carolyn. So what were the results of this study? Dr. Carolyn Lam: In Emperor-Preserved, baseline health status and quality of life did not influence the magnitude of effect of empagliflozin on the risk of cardiovascular death or hospitalization for heart failure. Empagliflozin improved health status and quality of life as assessed by the Kansas city cardiomyopathy questionnaire across all domains and at all measured time points. Thus an effect that appeared early and was sustained for at least one year. Dr. Greg Hundley: Very nice. So two really informative papers on SGLT2 inhibitors. Well Carolyn, I'm going to turn the conversation to the world of preclinical science and talk about Titin. So Carolyn, titin truncation variants are the most common inheritable risk factor for dilated cardiomyopathy and their pathogenicity has been associated with structural localization. The A-band variants with overlapping myosin heavy chain binding domains appear more pathogenic than the I-band variants and the mechanisms for this are not well understood. So these investigators led by Dr. Hinson at the Jackson Laboratory for genomic medicine, performed a study demonstrating why A-Band variants are highly pathogenic for dilated cardiomyopathy and how they could reveal new insights into dilated cardiomyopathy pathogenesis. Titin functions and therapeutic targets were assessed. Dr. Carolyn Lam: Wow, interesting. So what did they enroll in? How did they do this? what did they find? Dr. Greg Hundley: Great Carolyn, so human Cardiomyocytes and cardiac micro tissue functional assays revealed that highly pathogenic A-Band Titin truncation mutations generate four shortened titin poisoned peptides and diminish full length, titin protein levels. While less pathogenic I-band titin mutations only diminish titin protein levels. And so Carolyn, the authors developed a one and done, genome editing therapeutic approach using CRISPR technology to repair the reading frame of Titin truncation mutations in cardiomyocytes. And therefore these genome editing therapeutics could correct the underlying genetic lesion responsible for dilated cardiomyopathy due to these Titin mutations. Dr. Carolyn Lam: Wow. Interesting. One and done genome editing. You learn something new every day with circulation. You've got another paper? Dr. Greg Hundley: Yes, Carolyn. Thank you. And so this paper comes to us from Dr. Beiyan Zhou From the Yukon health, school of medicine and again, from the world of preclinical science. So Carolyn, while several interventions can effectively lower lipid levels and people at risk for atherosclerotic cardiovascular disease, cardiovascular event risks remain, suggesting an unmet medical need to identify factors contributing to this cardiovascular event risk. Now monocytes and macrophages play central roles in atherosclerosis, but previous work has yet to provide a detailed view of macrophage populations involved in increased atherosclerotic cardiovascular disease risk. Dr. Carolyn Lam: Huh? Okay. Well, I'm super excited to hear what these investigators did Greg. Dr. Greg Hundley: Right, Carolyn. Well these authors developed a novel computational program. They call AtheroSpectrum, which identified a specific gene expression profile associated with inflammatory macrophage foam cells. And additionally, a subset of 30 genes expressed in circulating monocytes jointly contributed to the prediction of symptomatic atherosclerotic vascular disease. So therefore Carolyn, in the future, perhaps incorporating this new pathogenic foaming gene set with known risk factors may significantly strengthen the power to predict atherosclerotic cardiovascular disease risk. Dr. Carolyn Lam: Wow. Super interesting and well summarized. Thank you, Greg. Well also in today's issue, there's a Perspective by Dr. Kirtane on “The Long-Awaited Revascularization Guidelines are Out. What's In Them?” A Research Letter by Dr. Laffin on rise in blood pressure observed among us adults during the COVID 19 pandemic. Dr. Greg Hundley: Very Nice Carolyn. Well in our Cardiovascular News Segment, there's a piece on metabolic risk factors and how they drive the burden of Ischemic heart disease. Well, what a great issue here and now, how about we get onto that feature discussion? Dr. Carolyn Lam: Very Cool. Closure devices after TAVR. Here we go. Dr. Greg Hundley: Well, listeners welcome today to our feature discussion and we have with us Dr. Mohamed Abdel Wahab from Leipzig Germany. And we are going to discuss some issues pertaining to transcatheter aortic valve replacement, in terms of access to the arteries in the lower extremity. Welcome Mohamed. And can you start with, what was some of the background that led you to perform your study and what was the hypothesis that you wanted to address? Dr. Mohamed Abdel-Wahab: Thank you, Greg. And thank you for having me here. So as you mentioned, there are several cardiovascular procedures that currently require large-bore arterial access. The most common of these procedures is transcatheter aortic valve replacement. But there are other procedures as well, like endovascular aortic repair, mechanical circulatory devices. All of these require large-bore arterial access and of course, closure afterwards. And what we were interested in looking at was whether different types of vascular access site closure devices or strategies behave differently in the setting. Particularly in the setting of transcatheter aortic valve replacement. The reason behind this is that for many years, we only had one technique, to percutaneously close arterial access sites after these procedures. And these were mainly based on suture based devices or suture based techniques. Very recently, alternative techniques based on collagen plugs have been introduced. Dr. Mohamed Abdel-Wahab: And we know these types of devices or closure techniques from usual coronary intervention procedures for smaller access sites or for smaller sheath size. But they have been developed a step further for these large-bore procedures. These newer devices, particularly what we call the MANTA device, which is based on the collagen plug has been shown in initial visibility studies and also in registry based analysis to be very safe and effective. It leads to a very rapid hemostasis. And data from observational studies have suggested that it may be even superior to the suture based techniques, largely based on what we call the ProGlide device or the [inaudible 00:10:56]. And this is actually what we were aiming to look at. To compare these two different strategies based on two different devices. The suture based, the classical suture based technique using two ProGlides compared to the newer plug based technique using the MANTA in a population treated with TAVR. Dr. Greg Hundley: Very nice. And describe for us, your study design. And then also maybe explain a little bit more about the study population. Who did you include in this study? Dr. Mohamed Abdel-Wahab: So the design was more or less, very inclusive. So we designed the trial to more or less represent real word population. More or less [inaudible 00:11:40] population receiving transcatheter aortic valve replacement. So we included patients, of course where the procedure is being thought to be indicated and feasible by a multidisciplinary heart team. And also where the heart team thought that the transfemoral access route, which is the main route for the majority of patients, is obtainable and use of a percutaneous closure device is also possible. Dr. Mohamed Abdel-Wahab: Of course we had some exclusions. For example, patients where the use of a surgical access technique was necessary. They couldn't be naturally included in the trial. Patient that already had complications related, for example, to previous coronary angiogram PCI at the access site, they couldn't be included. But we were more or less, very inclusive in this trial. The trial population reflects the patients that are currently being treated with TAVR, so more or less an elderly population. More or less equally split-by males and females, which is very particular, again to the TAVR population. So this is a little bit different than the population that receives PCI, where we usually have a predominantly male population. This is not the case here. So these are the broad lines. Also reflecting current practice, the population that has been included in the trial is more or less overall, an intermediate risk population, when you look at the surgical scores. Dr. Greg Hundley: Very nice. So this was multicenter and then also patients were randomized to each of the two therapies, I believe. And was that a one to one randomization? Dr. Mohamed Abdel-Wahab: Exactly. So it was a multicenter trial. Patients were randomized between these two techniques. We mentioned the ProGlide based and the MANTA based in 1:1 fashion. And steering committee of course was more or less dominated by interventional cardiologists. Of course, in the context of this particular trial setting, the trial was only performed in Germany and it was an investigative initiated trial, not sponsored by the industry. Dr. Greg Hundley: Very nice. And can you describe for us, Mohamed, your results? Dr. Mohamed Abdel-Wahab: Yes. We actually hypothesized based on the observational data we have, that we will have less vascular complications with the MANTA based technique or the collagen based technique. At the end of the day, what we observed is completely the opposite. So the primary endpoint of the trial, which was what we call major and minor vascular complications defined according to the standardized criteria provided by the valve academic research consortium. These events occurred significantly more common in patients that were randomized to the MANTA based technique, as opposed to the ProGlide based technique, which was statistically significant. Dr. Greg Hundley: And did you observe those results across both the men and the women? And also, were there any differences in the results related to participants' age? Dr. Mohamed Abdel-Wahab: Yeah. So there were no interactions with various subgroups, both the predefined ones, including age and sex, as you mentioned. But also we looked at some post hoc subgroups, including for example, whether this is being affected by the size of the access vessels or by the presence and location of calcification, for example. But there were no interactions in all subgroups we looked at, with one exception which was chronic renal insufficiency. But all other subgroups showed actually no significant interaction, favoring the suture based, ProGlide based technique in all subgroups. Dr. Greg Hundley: Very good. And so can you describe in terms of, for individuals performing TAVR procedures and obtaining access, how do we use the results of your study to inform how we might move forward with closure of the artery in the future? Dr. Mohamed Abdel-Wahab: I mean, the first thing I would like to stress is the importance of doing randomized trials in general. Because I think this is not the first time we see opposite results when we are comparing randomized evidence with the evidence from observation studies, with the known limitations of observational comparative analysis. The second thing I think is really reassuring that the suture based technique that we know and that we have been using for many years now is safe and appears to be even more effective than the newly developed plug based technique. So this is one important information I think from this trial. The third piece of information is that the recently developed plug based technique, although being inferior in the study, it still may have some advantages in selected patients. And this is what we probably need to look at in a little bit more details in the future. Dr. Mohamed Abdel-Wahab: For example, what we realized from the study is that it could be a good option as a bailout device. So in some cases where the suture based technique has failed in the study, the crossover to the MANTA device was successful in the majority of cases. And may lead or help avoid complex endovascular interventions and implanting for example, stents or covered stents or even doing surgery. So this is something that is a nice observation from the dataset we have, but of course needs validation in larger studies. Dr. Greg Hundley: Very nice. And so really you've answered, kind of one of our key questions is, your thoughts on the next study that you see needs to be performed really in this area of research? Dr. Mohamed Abdel-Wahab: Yeah, so I think there are several things. One thing is, again, to look at potential patient subgroups that may benefit from the plug based device from the beginning. So probably it's not something that we should be using as a default strategy based on the results of this trial. But there could be certain subgroups we need maybe to dig a little bit more into the details or subgroups, if you wish to say so. Look a little bit more granularly at some patient groups that could benefit. But as mentioned, I think that the bailout indication is a very interesting one and needs to be looked at. Dr. Mohamed Abdel-Wahab: Not only in the TAVR setting, but also in the setting of other procedures. Such as for example, the use of mechanical circulatory assist device or ECMOs, where it may be difficult to apply these sutures post hoc. So the sutures that we apply during a TAVR procedure and what we use in this trial, this is the so-called preclosure technique. So you apply the sutures after gaining access. Then you insert your large-bore sheaths through the procedure. And then the sutures are already there and you can close the access site, usually without problems. Which is difficult, if you obtain access, for example, with an ECMO or an Impella. And then after a couple of days, you need to close it. So the sutures are not yet in place. In this particular scenario, it may be beneficial to use a plug afterwards. Or as a bailout device as previously Mentioned. Dr. Greg Hundley: Very nice well listeners. We want to thank Dr. Mohamed Abdel Wahab from Leipzig Germany for bringing us this study indicating that among patients treated with transfemoral TAVR, this pure plug based vascular closure technique using the MANTA VCD was associated with a higher rate of access site or access related vascular complications. 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 AHA journals dot org.

#101 masa bahagia bersama : Ratu Ember, Titin, Madona, Neneng dan Iis --- Send in a voice message: https://anchor.fm/francis-underwood/message

En este nuevo programa del podcast Hola Mundo, hablamos del road trip que hicimos por la isla norte de Nueva Zelanda. Además, contamos la opinión de Angie de titinroundtheworld.com. En este programa podrás encontrar: • El tío del fondo del dora (parte I)• Radiografía de Nueva Zelanda• Aquella vez que recorrimos la isla norte de Nueva Zelanda en coche• "Seguro qué..." by Chapka Assurances • Lo más raro que NO vimos en Nueva Zelanda fue... • Lo más bonito que vimos en Nueva Zelanda fue…• Recuerdas cuándo… • El tío del fondo del dora (parte II)• La opinión "con fundamento" Angie de titinroundtheworld.com / @titinroundtheworld• Videotontuna Viajera #78 Si te está gustando esto de escucharnos y vernos haciendo podcast, comparte y dale al boca a boca. No te quedes con las ganas y suscríbete en tu plataforma favorita: apple podcast, ivoox, spotify, castbox o google podcast. Y si eres muy de YouTube porque además quieres "verlo", suscríbete a nuestro canal. Aquí puedes ver la primera temporada: https://www.youtube.com/watch?v=RrIXXcLVrK8&list=PLpFNz2S2UB5yh5MOOq4UlA9BHnRI1W1Y2&t=0sAquí, la segunda temporada: https://www.youtube.com/watch?v=7DsYdnt4aLg&list=PLpFNz2S2UB5yr7Jw3JYXoIioACqSNjFKF&t=0sUna vez más, gracias a Chapka Assurances que nos apoya en esta nueva aventura y que por otra parte, te ofrecen un 7% de descuento con el código MUNDO al contratar tu seguro con ellos en: https://www.chapkadirect.es/?app=cd_aqr Quizás también te pueda interesar ver alguno de nuestros cortometrajes o documentales viajeros: - El síndrome del eterno viajero I: https://www.youtube.com/watch?v=7dKGcg_jBhw&t=0s- El síndrome del eterno viajero II: https://www.youtube.com/watch?v=uq5uQCFrNGw&t=4s- Hola, Mundo (el documental): https://www.youtube.com/watch?v=rGSLv0PjgF0&t=1164s- Anoniman, detrás de los carteles: https://www.youtube.com/watch?v=hjTnlejAgcI&t=52s Por si te ha llegado el rumor de que hemos escrito tres libros. Sí, es cierto. Son “Tontunas Viajeras”, “Algo que recordar viajando con mochila" y "Algo que recordar viajando con bebé" y los puedes conseguir en: https://algoquerecordar.com/posts-destacados/siete-anos-en-dos-libros/ y https://algoquerecordar.com/ocurrencias/libros/tontunasviajeras-el-libro/A nosotros puedes seguirnos en nuestro blog algoquerecordar.com o en todas las redes con @algoqrecordar ¡Hasta el próximo programa! Lucy&Rubén

Troisième programme de MICHEL TITIN-SCHNAIDER pour webSYNradio : Diptyques. Le travail musical de Michel Titin-Schnaider se caractérise par l'utilisation d'instruments virtuels comme sources sonores. Les diptyques illustrent cette démarche: chaque diptyque est constitué d'une première partie « instrumentale » avec très peu d'effets de transformation du son. Puis d'une 2e partie qui utilise comme « matériau de base » la première partie dans son intégralité.

This week’s episode features author Emma Birks and Associate Editor Hesham Sadek as they discuss the article " Prospective Multicentre Study of Myocardial Recovery Using Left Ventricular Assist Devices (REmission from Stage D Heart Failure: RESTAGE-HF): Medium Term and Primary Endpoint Results." TRANSCRIPT BELOW: Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center of VCU Health in Richmond, Virginia. Carolyn, our feature article this week, we're going to examine myocardial recovery using left ventricular assist devices, getting some early results from the RESTAGE-HF study. But before we jump to the feature discussion, how about we discuss some of the papers in the issue? Would you like to go first? Dr. Carolyn Lam: Yes I would. Have you thought about what's the benefit of emergent coronary angiography after resuscitation from out of hospital cardiac arrest for patients without ST elevation? It's an important question. Well, the portal study was reported by Dr. Kern from University of Arizona and colleagues, and this was designed to evaluate the efficacy and safety of early coronary angiography and to determine the prevalence of acute coronary occlusion in resuscitated out of hospital cardiac arrest in patients without ST elevation. So adult comatose survivors without ST elevation after resuscitation, were prospectively randomized to early coronary angiography versus no early coronary angiography, where early was defined as less than 120 minutes from arrival at the PCI capable facility. The primary endpoint was a composite of efficacy and safety measures, including efficacy parameters of survival to discharge favorable neurological status at discharge echo measures of left ventricular ejection fraction, more than 50% and a normal regional wall motion score within 24 hours of admission. Dr. Greg Hundley: So, lots of data here. What did they find? Dr. Carolyn Lam: So, unfortunately the study was prematurely terminated before enrolling the target numbers of patients. A total of 99 patients were enrolled from 2015 to 2018 and 49 were randomized to early coronary angiography. The primary endpoint of efficacy and safety was not different between the two groups. Early coronary angiography was not associated with any significant increase in survival or adverse events. And early coronary angiography revealed a culprit vessel in 47% with a total of 14% of patients undergoing early coronary angiography, having an acutely occluded culprit coronary artery. So while this was an underpowered study, when considered together with previous clinical trials, it does not support early coronary angiography, comatose survivors of cardiac arrest without ST elevation, whether early detection of occluded potential culprit arteries leads to interventions that improve outcomes does require additional study. And this is discussed in an editorial by Dr. Lemkes from Amsterdam university medical center. Dr. Greg Hundley: Very nice Carolyn. So at least the study that points us toward the next study that has to be performed and also does with other studies provide a little more clarity. Well, my next paper is from Professor Sanjiv Shah and--oh, wait a minute! And also from you as a co-author. Well, Carolyn, how about we have a little mini feature discussion where I can ask you some questions and then you can tell us all about your paper. Dr. Carolyn Lam: Happy to. Dr. Greg Hundley: Great. So Carolyn, what hypotheses were you testing and what was your study design and who was included in your study population? Dr. Carolyn Lam: Okay. So the question was we wanted to answer was thus a systemic pro-inflammatory state as indicated by proteomic profiling. Does that mediate the association between comorbidities and normal cardiac structure and function in HFpEF. To answer that we studied 228 patients with HFpEF from our multicenter promis HFpEF study. And these patients had 248 unique circulating proteins quantified using the old link multiplex immunoassay. Now I'm going to describe a complex analysis, but we basically had to first perform principal component analysis. And we did this to summarize 47 proteins known a priori to be involved in inflammation, and then used unbiased network analysis of all the 248 proteins to identify clusters of proteins that over-represented inflammatory pathways. We then used a mediation analysis to determine whether and to what extent inflammation mediates the association of comorbidity burdens with abnormal cardiac structure and function. And finally, we externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without HFpEF. Dr. Greg Hundley: Wow Carolyn, such a great design and an app machine learning mediation analyses, and then validation in an independent cohort. So tell us, what did you find? Dr. Carolyn Lam: So first, comorbidity burden was associated with abnormal cardiac function and structure and with these principle components of clusters of inflammation proteins. Second, systemic inflammation was associated with echo indicators of worse hemodynamics, like higher EDE' ratio and worse, right ventricular function. And third, inflammation indeed mediated the association between comorbidity burden and many of these echo parameters with, and I'm going to name a couple of routines. So TNF-R1, uPAR, IGFBP-7 and GDF-15 being the top individual mediating proteins. In the validation cohort inflammation was up-regulated in HFpEF compared to controls and the most prominent inflammation protein cluster identified was also the same one as in PROMIS-HFpEF. Dr. Greg Hundley: Beautiful Carolyn. So with these new proteins identified, what's the take home message here? Dr. Carolyn Lam: Here it is. Proteins involved in inflammation form a conserved network in HFpEF. And this was found across two independent cohorts. This may mediate the association between comorbidity burden and echo indicators of worst hemodynamics and right ventricular dysfunction. In totality, these findings support the comorbidity inflammation paradigm in HFpEF. Dr. Greg Hundley: Great job Carolyn, I liked the mini feature. That was so nice having one of the authors of the study here to explain kind of a two for one here, because we're going to get a feature and a mini feature. Have you got another paper you want to tell us about? Dr. Carolyn Lam: Thanks Greg and that works both ways. This next paper provides insights into the identity origin and function of many cells that make up late stage atherosclerotic lesions. It also identifies the mechanisms by which these control plucks stability. So corresponding author, Dr. Owens from Virginia School of Medicine and colleagues conducted a comprehensive single cell RNA sequencing of advanced human carotid endarterectomy samples, and compared these with murine micro dissected advanced atherosclerotic lesions with smooth muscle cell and endothelial lineage tracing to survey all plaque cell types and to rigorously determine their origins. Dr. Greg Hundley: Carolyn you know, this is another great study where we have both human subjects research and small animals. What were their results? Dr. Carolyn Lam: They provided evidence that smooth muscle cell specific knockout of transcription factors, KLF4 versus Oct-4 showed virtually opposite genomic signatures and their putative target genes played an important role, regulating smooth muscle cells phenotypic changes. They also provided evidence that smooth muscle cell derived cells within advanced mouse and human atherosclerotic lesions exhibited far greater phenotypic plasticity than generally believed, with KLF4 regulating the transition to multiple phenotypes, including LGALS 3 plus osteogenic cells likely to be detrimental for late stage atherosclerosis plaque pathogenesis. So in summary, smooth cell phenotypic switching produces cells that can be beneficial or detrimental to lesion stability and may be an important mechanism controlling the risk of unstable atherosclerotic plaque and myocardial infarction or stroke. Dr. Greg Hundley: Oh, great job, Carolyn. Well, the next paper I have is from Professor Muredach Reilly from Columbia University. And Carolyn smooth muscle cells play significant roles in atherosclerosis via phenotypic switching, a pathological process and with smooth muscle cell D differentiation, migration and trans differentiation into other cell types yet how smooth muscle cells contribute completely to the pathophysiology of atherosclerosis remain somewhat illicit. So the authors sought to reveal the trajectories of smooth muscle cell trans differentiation during atherosclerosis, and to identify molecular targets for disease therapy by combining smooth muscle cell fate mapping and single cell RNA sequencing of both mouse and human atherosclerotic plaques. Dr. Carolyn Lam: Echoing what you said earlier, Greg, both animal and human data. Terrific. So what were the results? Dr. Greg Hundley: The authors found that smooth muscle cells transitioned to an intermediate cell state during atherosclerosis, which was also found in human atherosclerotic plaques of carotid and coronary arteries. Smooth muscle cell derived intermediate cells termed stem cells were multiphoton and could differentiate into macrophage like and fibro chondrocyte like cells as well as returned towards the smooth muscle cell phenotype. Retinoic acid signaling was identified as a regulator of the transition of smooth muscle cells to stem cells and RA signaling was dysregulated in symptomatic human atherosclerosis. Finally Carolyn, human genomics revealed enrichment of genome-wide association study signals for coronary artery disease in RA signaling target gene low PSI and correlated between coronary artery disease risk levels and repressed expression of these genes. Now, activation of RA signaling by all trans retinoic acid and the anticancer drug for acute promyelocytic leukemia blocked the smooth muscle cell transition to stem cells, and that also reduced atherosclerotic burden and then promoted fibrous cap stability. So a lot of clarification of the role of smooth muscle cells, trans differentiation and the development of atherosclerotic disease Dr. Carolyn Lam: Indeed and translational implications. Interesting. Now let's review some of the other papers in this issue. Shall we? First as an, on my mind paper by Dr. Kullo on familial hypercholesterolemia, a reportable disorder. There's an exchange of letters between doctors Lazzerini and Li regarding the article autoantibody signature in cardiac arrest. Dr. Greg Hundley: Thanks Carolyn. Well, I've got a couple other papers to tell you about really a series of research letters from the mailbag. So first Daniel Modin has a Research Letter entitled “Acute COVID-19 and the Incidents of Ischemic Stroke and Acute Myocardial Infarction.” Dr. Christian Mueller has a Research Letter entitled “Effect of a Proposed Modification of the Type 1 and Type 2 Myocardial Infarction Definitions on Incidents and Prognosis.” And finally Carolyn a Research letter from Dr. Jizheng Wang involving an East Asian-specific common variant in TNNI3 that appears to predispose to hypertrophic cardiomyopathy. Well, Carolyn, what a great issue and thank you for that many feature, but how about we proceed on next to our feature discussion? Dr. Carolyn Lam: Let's go, Greg. Today's feature paper is one of those that I think is going to change clinical practice. So please listen up. It's about the RESTAGE-HF study. So pleased to have with us the first and corresponding author, Dr. Emma Birks from University of Kentucky Gill Heart and Vascular Institute, as well as our associate editor, Dr. Hesham Sadek from UT Southwestern to discuss this very important paper. Emma, could you please describe the RESTAGE heart failure study? Dr. Emma Birks: Let's say prospective study of patients getting left ventricular assist devices. So patients with very advanced heart failure are receiving left ventricular assist devices as either a bridge to transplant or as destination therapy. And they're seeing them for chronic heart failure because really all other medical therapy has failed and we use the pump to try and recover their own heart. So when the pump's implanted, we optimize the LVAD unloading, the maximum loading, and we give them a very aggressive medical therapy regime, unless they may not have tolerated these medications before because of poor blood pressure and renal dysfunction, we find they do tolerate them. So we give them in very aggressive doses and then we monitor their underlying function at regular intervals and try and promote recovery. So with that, we had done this in England in the past, in a single center study, but it had not yet been reproduced, which was obviously essential to have a bigger impact. Dr. Emma Birks: So we did a prospective study of six big US centers. We found that we've created a primary endpoint that was statistically powered in advance. And the primary endpoint was the number of patients that recovered within an 18 month period, that were explanted and remained off the pump and alive without transplant over for one year. So overall we found that of the 40 patients we recruited in the centers with chronic heart failure, we were able to explore 19. Of those that satisfied the primary endpoint, that was actually 40% of patients, with 52.3% being explanted overall. And importantly, patients were explanted in all six centers, so we found that the protocol was reproducible under the how much higher rate of recovery that you would otherwise see. Normally there is a database in the US that tracks outcomes from bad patients. And generally only 1-2% seemed to recover enough to be explanted generally. So this was a much bigger percentage. Dr. Carolyn Lam: Emma, first of all, congratulations, what an important trial and what stunning results. More than half of patients receiving that protocol were explanted. That's just remarkable. Now, could I just ask, what is it that you did that was different? I noticed you spent a lot of time saying this was an aggressive pharmacological protocol that was along with the LVAD unloading. Could you maybe elaborate on that a little bit more? Dr. Emma Birks: Yeah, I think that was a very important part of it. So generally I think when the LVAD goes in most centers, the patients are very sick, so most of those patients wouldn't then try and recover them or look at underlying functions. I think that was the first thing that was different was to try very hard. And then we had centers, the experience, I had done this before, it was also very helpful, all agreeing to do the same thing. We use a very aggressive regime of ACE inhibitors, Beta blockers, auto serotonin antagonists and ARBs. And that was also an unusual thing. We use the fact that they're supported with the pump to use both an ACE and an ARB together, but the idea that they have better blood flow in the cranial is way more tolerant and we give very high doses. So we use Lisinopril with the target dose of 40 milligrams, Coreg with a target dose of 50 BID, Aldactone 25 milligrams daily. Dr. Emma Birks: And then we add in losartan if they tolerate it and actually aim for 150 milligrams daily, so those doses are very high. And I think not normally given to people on LVADs. So you must've had the LVAD that don't tolerate the medical therapy and stop it. They might just have blood pressure control, etc. There is now also another INTERMACS trial, a sort of big study that's come out that actually shows benefit of neurohormonal antagonists in general. So that goes together with our study to show that they should already be given and then the regular testing. So we had quite thorough testing. So first of all, we do echos on the pump and then we do echos with the LVAD turned down to a speed at which is not contributing. So we do that and we do an echo at five minutes with it down 15 minutes, and then we walk the patient, distress them. Once we show that the hearts come down in size and improved function, then we do an exercise test, right heart cath on an off pump to look at the hemodynamics. Dr. Carolyn Lam: Wow. So tremendous effort and really the protocol is unique in and of itself, not just the pharmacological therapy, also the way this is monitored and decisions are made really, really amazing. Just one last question for me, because it's a humbling reminder of the importance of neurohormonal blockade in these patients. Do you continue that after they're explanted? Dr. Emma Birks: Yes, we do. And we continue aggressively and that's slightly different as well in that normally you wouldn't give a patient a nascent an up of course, but given that they've already tolerated it on the pump in that same patient. So we restart the same drug regime afterwards, and we actually like to get them to quite along that dosage before we discharge them from the XPLAN, we don't want to do that slowly. We get them back on it quite quickly. And then we follow them very carefully because we don't really know the long-term durability. Dr. Carolyn Lam: Wow, thank you. Hesham. I would love your thoughts on this paper. I mean, it really, really is remarkable results. Dr. Hesham Sadek: Yeah. I mean, I was very happy that we received this paper to review, frankly I've been following that work for a long time since the first new England paper that came out and I'd like to congratulate you for an amazing work. I think this will change the field. First, how was this trial different from the first trial, other than the fact that it's multicenter, what would you say are the major changes that you made to the protocol and what you've learned since the first trial? Dr. Emma Birks: Yes, you're absolutely right. We did make some changes. So first of all, it was six sites instead of one site. I think it was very important to reproduce it in the US but we changed the protocol itself as well. The first trial had optimization of the LVAD speed, really just by echo looking at the reduction in the ventricle size. It had the aggressive medical regime was very similar except this time we increased the Losartan dose from 100 to 150 after the Hill's trial came out. The testing was very frequent in the original English Sheffield study, probably a little bit too frequent to be able to be adopted on a wide scale. So we tried to reduce it down a little bit. So we decrease the frequency of the low-speed echos. I think we had them at six weeks, four months, six months, nine months in a year. Dr. Emma Birks: And after that, we saw if they were already improving and started and only did them at a year to 18 months, if they were improving. And then we also cut down the number of exercise tests. So we didn't do the exercise test until the echo was already showing significant improvement. For two reasons, one, we didn't find it very reliable and two, it was just too much testing for the patient. So it was more of a confirmatory test. In fact, it wasn't a requisite for a pump explantation. We didn't do a left heart catheter, which we did before. Previously we tried to measure LVEDP, this time we decided which was enough. So we just did a right heart cath on and off pump. And we did that once the echo was improved as well. So we rationalized that a little bit. And then the other important thing was before in hayfield study, once we saw the ventricular size come down and injection fraction start to improve, we actually added in Clenbuterol, which was a Beta-2 agonist. Dr. Emma Birks: And the idea with that was to cause a kind of physiological hypertrophy so that when you took the pump out, the heart didn't just dilate. We were worried about atrophy at the heart on the pump long-term. So we did that to try and improve the durability of recovery. So the reason we left off this time was really the previous protocol was very good, but was very complicated. So we wanted to see what rate of recovery we could get just with the aggressive reverse remodeling, neurohormonal drugs, plus the aggressive testing and the optimum loading with the idea that later on, we could add on either Clenbuterol or something later to improve the durability of recovery, if the ability of recovery is not good enough, but actually so far it's proven to be pretty good because the study itself takes quite a long time. It was sort of to recruit them. We had an 18 month period than the follow-ups. It was already a multi-year study. So we wanted to establish a regime that many centers could use to try and promote recovery. Dr. Hesham Sadek: I want to follow up on that last point, because as you know, I've looked at some of these Heights as well in our center, and we looked at the results with you and Stavros and others. So the myocytes size is expected to change, decrease with unloading, right with sufficient unloading. So how would you prepare the Myocardium to take on the normal afterload if you are not going to induce by a beta agonist, for example, Dr. Emma Birks: What I would like to do in the future is try using the pump itself actually. Sometimes there's heart recovers, the heart shrinks and actually start opening their own valve and working in the heart. Of course, when you have the HeartMate one, actually, sometimes wasn't synchronous with the heart. So sometimes the heart will beat against the pump anyway. Once you go to the continuous flow pumps, you've got continuous unloading. So I think it'd be very interesting to intermittently turn down the pump speed and load the heart to work it before you take the pump out. So I would really like to do that. I think that might be the next interesting phase of the study to improve your ability to.. So I guess once you've got maximum reverse remodeling and improvement in function, you could just turn the pump speed down to let the valve open. Dr. Hesham Sadek: Do you think perhaps if you do that, you will increase the percentage of patients that can be explanted? Do you think that could be a factor in the percentage of patient that can be explained? Dr. Emma Birks: I think it might be, it might more improve the, to your ability to make sure we have for a long, good echo function afterwards. Dr. Hesham Sadek: That's great. So another question this was limited to not ischemic cardiomyopathy patients. Can you elaborate a bit on why not include, for example, revascularized ischemic cardiomyopathy patients. Dr. Emma Birks: Yeah, so we did that really just because we didn't want to change too much from the original protocol. We also stuck with one device because we thought if you have multiple pumps, multiple diagnosis, it does get hard to analyze in a multicenter trial. So we did that on purpose and we were always trying to simulate the bridge to transplant population in the age group too. But actually interestingly, most of the patients recruited in the trial were destination therapy patients in the end. Dr. Emma Birks: I think this could be done with ischemic cardiomyopathy. I think we don't have enough data on ischemic cardiomyopathy to know whether it does or it doesn't recover. So I don't think our results say that it's only known as ischemics. I think it just means we haven't studied ischemics sufficiently. Logically they might have more scarred. It might be harder to get such a good percentage to recover. I think all of us in our individual centers have seen a few and we've sort of seen the on pump echo improved, and we've tested them and then taken some out. But most of these cases are anecdotal. So I think that is another important study that needs to be done, obviously a large group of patients. Dr. Hesham Sadek: I agree. So given that they're not ischemic cardiomyopathy, do you know how many of them had genetic testing or what is the percentage of monogenic cardiomyopathys or how do you think these patients would respond to this protocol? Dr. Emma Birks: But if you had a familiar history and actually found it didn't make any difference, whether they recovered or not. I think some of us have personally seen actually those were the familial cardiomyopathy tend to recover more actually again, anecdotally. We published a people before looking at the Titin gene saying that that did recover. I think actually only five of these patients, 12% of them had a family history, but some of them recovered Dr. Hesham Sadek: One final question, as you know, I'm a basic scientist. So ultimately the question I'm going to ask, what do you think the mechanism is? Is it that these hearts are just in a vicious cycle of remodeling and validation, increased pressure, and you were sort of giving it a chance for actual structural reverse remodeling where you changed the geometry of the myocardium and perhaps rest of myocardium, allow for improvement of calcium cycling dynamics, or do you think, is something more exciting? Like three-generation for example. Dr. Emma Birks: Yeah, that's very interesting because I think the LVAD doesn't unload, so it shrinks the ventricles. I think it does improve the geometry and the dynamics. And then you use the drugs where they may have felt before you almost put them from class four, heart failure into class three with the bad to give that chance to work again. And then I think various cellular and fibrotic factors have been looked at and it's hard because there was so many factors have been looked at that. You were going to find some that go up and some that go down and what's important. But the impression I get overall is that you do get improvement, the matrix limits, the recovery on the fibrosis and the matrix. Whereas you do get improvements of myocardial function and cellular function. The cells will tend to reverse the dysfunction and it's really whether that happens or not. It's probably limited a lot by the matrix Dr. Carolyn Lam: That is amazing here. Hesham, I'm going to put you on the spot. Do you have your own hypothesis about this Dr. Hesham Sadek: Based on the work that they did initially in the new England paper, we did actually a small pathology study looking at cell cycle of cardiomyocytes from the core samples and from the explanted hearts post-transplant and we saw evidence of increased cardiomyocytes cell cycle in these patients along with decreased DNA damage and some metabolic remodeling as well with mitochondria. So, you can't really tell much from tissue whether you regenerated it or not, but as you know myocytes don't divide and this is the basis for the lack of spontaneous regeneration of the myocardium. So if this in fact removes the block to cardiomyocyte cell cycle, then this might be a regenerative therapy mechanism. Dr. Carolyn Lam: Well, this is amazing. I wish we had all day to discuss this more. I mean, this is the only place you can get a discussion that goes from clinical to basic signs and back to clinical. Thank you so much, Emma and Hesham for sharing today. Thank you audience for joining us today. You've been listening to circulation on the run on behalf of Greg as well. Don't forget to tune in again next week. Speaker 1: Program is copyright the American heart association, 2020.  

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Ayo Mendongeng: Kisah Katak yang Sombong , Titin Sutinah Dongeng Anak dari Moms untuk anak tercinta

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Laurene Lambertino-Urquizo was born and raised in Chicago’s south suburbs, and had 3 children. She studied Art History at several universities & taught on the college level. She volunteered on a research project at Field Museum for many years bringing light to a very rare and unknown collection of Precolumbian Mexican ceramics.Laurene enjoyed a normal childhood & adulthood until reaching the age of 50 when my medical problems began. She initially began experiencing difficulty in climbing stairs and respiratory muscle weakness, which her doctors believed was due to sleep apnea. She was fortunate to have excellent health care available through the University of Chicago Health Clinics and genetic testing for disease was still in its formative years.Laurene was first diagnosed with Inclusion-body Myositis (IBM) by two biopsies and EMGs. IBM is a form of Muscular Dystrophy that mostly affects adults beginning at middle age. The muscles weaken and deteriorate over time but typically it is not a fatal disease. There is no treatment, nor cure for it.  Almost twenty years later, due to evolving medical research and technology, she underwent genetic testing which revealed a new diagnosis of having a Titin Myopathy. The Titin gene is the largest gene in the human body and variants (mutations) to it can cause muscle weakness (especially in the legs and upper arms), respiratory muscle weakness, and cardiac issues (such as Cardiomyopathy). There is no treatment, nor cure for this currently and it is treated much the same as IBM by providing supportive services.Today she lives in a house fitted for someone with limited mobility and sleep with BiPap. She leads a full life and she enjoys reading, politics, her cats, and cooking.What We Talked About:Laurene describes the road to from being diagnosed with Inclusion Body Myositis to finding the correct diagnosis of Limb-Girdle Muscular Dystrophy. Limb-Girdle Muscular Dystrophy is caused by mutations in the TTN gene.Limb-Girdle Muscular Dystrophy (LGMD) has affected the muscles around her hips leading to the inability to lift her legs. She cannot climb stairs, lift herself out of a bathtub, or get up and down from a sitting position using only her legs. She relies on upper body strength and a walker. In addition, LGMD has affected her heart and lungs, resulting in cardiomyopathy and weakened respiratory muscles.Laurene talks about what it’s like to live with a chronic disease, her daily routine, the details of a good day and a not so good day.She educates us about why we need to be well informed, get the best possible healthcare, and advocate for ourselves.Laurene advises us not to take anything for granted. She tells us why she feels fortunate to be here.She talks about specific ways in which it is difficult to maneuver going out in public spaces and why it can be limiting for people with disabilities.Laurene believes in “the squeaky wheel getting the oil” so much, that she championed an initiative to outfit a hospital with appropriate accommodations for a person with disabilities after she had a bad experience during an appointment.She makes the case for medical cannabis and how it has helped her with her chronic pain.The Mindful Minute -Cobra pose instills courage and it strengthens your back muscles.Cobra pose in a chair - sit in mountain pose in a chair with a wide seat. Place your hands on either side of your hips, palms down and fingers pointing forward. Press your hands down into the seat (or make fists if that is uncomfortable for your wrists) and lift your chest and gaze to the ceiling. Make sure to keep the back of your neck long, about the width of your palm, so that your head does not fall back too far. Stay here for several breaths. To exit the pose, gently twist side to side with a straight spine.

Comentamos la situación del Xerez, de cara al próximo partido. Con las declaraciones de David Polaco y nuestro entrenador, Juan Carlos Gómez. Y en exclusiva la entrevista a Titin

Jane Ferguson:  Hi, everyone. Welcome to Getting Personal: Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine. It's May 2019, and this is episode 28. So let's see what papers we have in the journal this month.                              First up, a paper from Mengyao Yu, Nabila Bouatia-Naji and colleagues from the Inserm Cardiovascular Research Center in Paris, entitled GWAS-Driven Gene-set Analyses, Genetic and Functional Follow-Up Suggest Glis1 as a Susceptibility Gene for Mitral Valve Prolapse.                              In this paper, they set out to characterize the genetic contributions to mitral valve prolapse, or MVP, to better understand the biological mechanisms underlying disease. They applied the gene-set enrichment analysis for QWAS tool and the pathway enrichment tool DEPICT to existing GWAS for MVP in a French sample to identify gene sets associated with MVP. They find significant enrichment of genes involved in pathways of relevance to valve biology and enrichment for gene expression in tissues of relevance to cardiovascular disease.                              They zeroed in a Glis family zinc finger gene Glis1 with consistently strong pattern of evidence across the GWAS enrichment and transcription analyses. They replicated the association between Glis1 and MVP in a UK biobank sample. They found that Glis1 is expressed in valvular cells during embryonic development in mice, but is mostly absent at later times. They targeted two Glis1 orthologs in zebrafish and found that knockdown of Glis1 B was associated with a significant increase in the incidence of severe atrioventricular regurgitation. These data highlight Glis1 as a potential regulator of cardiac valve development with relevance for risk of mitral valve prolapse.                              Next up is a paper from Gina Peloso, Akihiro Namuro, Sek Kathiresan and colleagues from Boston University, Kanazawa University, and Mass General Hospital. In their paper, Rare Protein Truncating Variance in APOB, Lower LDL-C, and Protection Against Coronary Heart Disease, the team was interested in understanding whether protein truncating variance in APOB underlying familial hypobetalipoproteinemia confer any protection against coronary heart disease.                              They sequenced the APOB gene in 29 Japanese families with hypobetalipoproteinemia as well as in over 57,000 individuals, some with early onset CHD and some without CHD. They found that presence of an APOB truncating variant was associated with lower LDL cholesterol and lower triglycerides, and also with significantly lower risk for coronary heart disease. This study confirms that variance in APOB, leading to reduced LDL and triglycerides are also protective against coronary heart disease. :                            The next paper entitled Mortality Risk Associated with Truncating Founder Mutations in Titin comes to us from Mark Jansen, Dennis Dooijes, and colleagues from University Medical Center Utrecht. They analyzed the effect of titin truncating variance on mortality in Dutch families. Titin truncating variants are associated with dilated cardiomyopathy, but have a very variable penetrance.                              In this study, the authors looked at three titin truncating variants, established to be founder mutations, and traced the pedigrees back to 18th century ancestors. They looked at 61 individuals on the transmission line and 360 of their first-degree relatives. They find no evidence for excess mortality in variant carriers overall. However, when they restrict it to individuals over 60 years of age, they did find a significant difference in mortality, which was also observed in individuals born after 1965. What these data tell us is that these titin truncating variants have a relatively mild phenotype with effects on mortality only manifesting later in life in many carriers. Given increases in life expectancy over the past several decades, the prevalence of morbidity and mortality attributable to titin truncating variants may increase. Genetic screening may identify genotype-positive, phenotype-negative individuals who would benefit from preventative interventions.                              Continuing on the theme of genetic variance, we have a paper from John Giudicessi, Michael Ackerman, and colleagues from the Mayo Clinic, Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance. In this paper, they aim to find a better way to classify variants of unknown significance, of VUS, in the RYR2 gene. Variants in this gene are commonly associated with catecholaminergic polymorphic ventricular tachycardia, or CPVT.                              They examined 72 distinct variants in 84 Mayo Clinic cases and find that 48% were classified as VUS under ACMG guidelines. The rate was similar in a second sample from the Netherlands, with 42% of variants originally classified as VUS. They developed a diagnostic scorecard to incorporate a pretest clinical probability of CPVT, which included various clinical criteria, including symptoms and stress test results. Application of the phenotype enhanced ACMG criteria brought the VUS rate down to 7% in Mayo Clinic and 9% in the Dutch samples. The majority of VUS were reclassified as likely pathogenic.                              This study highlights how incorporation of disease-specific phenotype information can help to improve variant classification and reduce the ambiguity of reporting variants of unknown significance.                              We also have a number of research letters in the journal this month. From Karine Ngoyen, Gilbert Habib, and coauthors from Marseilles, we have a paper entitled Whole Exome Sequencing Reveals a Large Genetic Heterogeneity and Revisits the Causes of Hypertrophic Cardiomyopathy, Experience of a Multicentric study of 200 French Patients. In this study, they examined the genetic contributions to hypertrophic cardiomyopathy, or HCM, in 200 individuals as part of the HYPERGEN study and compared the benefits of whole exome sequencing compared with targeted sequencing of candidates' sarcomeric genes. All subjects had HCM documented by echocardiography.                              In the whole exome sequencing data, they first looked for mutations within 167 genes known to be involved in cardiomyopathies or other hereditary diseases. Of these 167 virtual panel genes, they find variants in 101 genes. Following whole exome sequencing, over 87% of the patients had an identified pathogenic, or likely pathogenic, mutation compared with only 35% of patients who only had targeted sequencing of sarcomeric genes.                              This highlights the generic heterogeneity of HCM and suggests that whole exome sequencing has utility in identifying variants not covered by sarcomeric gene panels.                              The next letter is from Wouter Te Rijdt, Martin [Vandenberg] and colleagues from University Medical Center Groningen and states that [dissynchronopathy] can be a manifestation of heritable cardiomyopathy. They hypothesized that left bundle branch block, also designated as dissynchronopathy, may be a manifestation of familial cardiomyopathy.                              They analyzed patients from a database of cardiac resynchronization therapy and identified super-responders whose left ventricular dysfunction was normalized by therapy. They carried out targeted sequencing in 60 known cardiomyopathy genes in 16 of these super-responder individuals and identified several variants, including a pathogenic variant in troponin T in one individual and variants of unknown significance in nine individuals. Pedigree analysis identified multiple family members with dilated cardiomyopathy.                              This study highlights that dissynchronopathy can be a manifestation of DCM, but that affected individuals may still benefit from cardiac resynchronization therapy.                              The next letter entitled Targeted Long-Read RNA Sequencing Demonstrates Transcriptional Diversity Driven by Splice-Site Variation in MYBPC3 comes from Alexandra Dainis, Euan Ashley, and colleagues from Stanford University. They set out to understand whether transcriptome sequencing could improve the diagnostic yield over genome sequencing in patients with hypertrophic cardiomyopathy. In particular, they hypothesized that long-read sequencing would allow for identification of alternative splicing linked to disease variance. They used long-read RNA and DNA sequencing to target the MYBPC3 gene in an individual with severe HCM who carried a putative splice-site altering variant in the gene. They were able to obtain heart tissue for sequencing and included several HCM and control subjects in addition to the patient with the MYBPC3 variant.                              They identified several novel isoforms that were only present in the patient sample, as well as some additional isoforms, including retained introns, extended exons, and an additional cryptic exon, which would not have been predicted based on the DNA variant. While the effects on protein function is not known, the transcripts are predicted to be translated.                              This analysis highlights the effect of a rare variant on transcription of MYBPC3 and provides additional evidence to link the variant to disease. This is a really nice approach, which could be used to probe causality and mechanisms, not only for cardiovascular disease, but for other rare variants in many disease settings.                              We finish with a perspective piece from Nosheen Reza, Anjali Owens, and coauthors from the University of Pennsylvania entitled Good Intentions Gone Bad, The Dangers of Sponsored Personalized Genomics. They present a case of a 23-year-old woman who presented for genetic counseling and evaluation after discovering she carried a likely pathogenic MYH7 variant associated with cardiomyopathy. She had no significant medical history, but had participated in employer-sponsored genetic testing motivated to identify potential variants related to cancer given a family history of cancer.                              After receiving her results, she experienced considerable anxiety and stopped exercising out of fear of cardiac complications. She visited an ER after experiencing chest pain, something she had not experienced previously. There was no appropriate counseling available at her institution for her genetic test results, leading her to seek out the additional counseling. Thus, while she was initially motivated to complete genetic testing because her employer offered it free of change, she ended up incurring costs related to the followup evaluation and counseling. Ultimately, she had no significant clinical findings. Although the variant had been listed as likely pathogenic, other sources consider it to be of unknown significance.                              This story highlights the psychological and financial impact that genetic testing can have on individuals, particularly when carried out without any pretest counseling or accessible post-test support when variants are identified.                              Despite the considerable promise of personalized medicine, there are many complexities to be considered, particularly with direct-to-consumer testing and employer-sponsored testing. This perspective highlights the ethical considerations and urges caution to maintain the best interests of patients.                              That's all for this month. Thanks for listening. I look forward to bringing you more next month.                              This podcast was brought to you by Circulation Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association 2019.  

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, also associate editor from VCU Health Systems, the Poly Heart Center in Richmond, Virginia. Dr Carolyn Lam:                So arrhythmogenic cardiomyopathy that will make most of us think of right ventricular disease and fatty infiltration of the muscle, but could arrhythmogenic cardiomyopathy really be a bi-ventricular disease? Well you've got to stay tuned to find out more in a fantastic interview coming right up after our little coffee chat. So Greg, what are your picks this week? Dr Greg Hundley:             My first paper is from Chris Lim at NYU in New York. And it's looking at the relationship between Mediterranean diet, air pollution and cardiovascular events.                                                 So, it's unknown whether usual individual dietary patterns can modify the association between long-term air pollution exposure and health outcomes. And so, in this large cohort with detailed diet information at the individual level, they had 548000 individuals across six states and two cities within the U.S. and a follow up period of 17 years. And that occurred between 1995 and 2011. And they evaluated whether a Mediterranean Diet modified the association between long-term exposure to ambient air pollution and then cardiovascular disease and mortality risk. And so, the average exposures to parts per billion and nitric oxide air pollution that the residential census track level were measured, and the investigators found that for the particulate matter there were elevated significant associations with cardiovascular disease. So, a hazard ratio of 1.13, ischemic heart disease similar hazard ratio and cerebrovascular disease with also a similar hazard ratio.                                                 For the nitric oxide, there were also significant associations with cardiovascular disease, as well as ischemic heart disease. And then the analysis indicated that Mediterranean diet modified the relationships. Those with a higher Mediterranean diet score had significantly lower rates of air pollution related mortality. These results therefore indicate Carolyn, that Mediterranean diet reduce cardiovascular disease mortality related to long-term exposure to air pollutants in a large perspective, U.S. cohort. Can you believe increased consumption of foods rich in antioxidant compounds actually may aid in reducing the considerable disease burden associated with ambient air pollution? Dr Carolyn Lam:                Oh wow. That is hugely interesting. Gosh, what do we do about this clinically now?  Dr Greg Hundley:            Remember, first of all, this is an associate study, so we can't infer cause effect. And what we need next are some more independent studies from other cities around the world, prospective cohorts, examinations of clinical outcomes and randomize interventions. And so, I think the results add to a growing body of literature suggesting that dietary patterns may help reduce cardiovascular events in these high air pollution exposure areas. And how does this work? Well, potentially through augmenting antioxidants and reducing oxidative stress. Dr Carolyn Lam:                That's really cool. So from one region, talking about air pollution to another region that often reports about air pollution and that's China. But this study from China is actually the largest registry study to evaluate sex related differences and hospital management and outcomes of patients with acute coronary syndrome in China.                                                 This is from corresponding author Dr Zhao from Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease. With colleagues of the improving care for cardiovascular disease in China, Acute Coronary Syndrome project, which is an ongoing nationwide registry of the American Heart Association and the Chinese Society of Cardiology. So, the authors use data from this project and evaluate at sex differences in the acute management, medical therapies for secondary prevention and in hospital mortality in more than 82000 patients admitted for acute coronary syndrome in 192 hospitals across China from 2014 to 2018. Dr Greg Hundley:             What did they show in this study? Dr Carolyn Lam:                They showed that women hospitalized for acute coronary syndrome in China less frequently received acute treatments and strategies for secondary prevention and had a higher in hospital mortality rate than men. Now the observed sex differences in this in hospital mortality were likely due to older age, worse clinical profiles and fewer evidence base acute treatments provided to women. And that's because the sex differences were no longer observed after adjustment for these clinical characteristics and acute treatments.                                                 What this all means though is specifically targeted quality improvement programs may be warranted to narrow these sex related disparities in patients with acute coronary syndrome in China.  Dr Greg Hundley:            Very interesting. I'm going to take sort of the next paper and it's looking at a different aspect of acute myocardial infarction. And these papers from Yong Wang from the Division of Molecular and Translational Cardiology at Hannover Medical School in Hanover, Germany.                                                 Now as we know, the heart can undergo deleterious changes and left ventricular geometry and function during that vulnerable period before scar formation has stabilized the infarct area. And so inflammatory cell trafficking from hematopoietic organs like the spleen to sites of tissue injury is coordinated by chemokine chemokine receptor networks. Therapeutically modulating these chemokine chemokine receptor interactions may promote infarct healing by limiting excessive inflammation induced tissue damage or by enhancing the recruitment of angiogenic cell populations to the infarct or the wound. Inflammatory cell trafficking after a myocardial infarction is controlled by a CXC motif chemokine ligand 12 or CXCL12 and its receptor CXC motif chemokine receptor 4. CXC receptor 4 antagonists, mobilize inflammatory cells and promote infarct repair. But the cellular mechanisms are unclear.                                                 So, what do these investigators do? In mouse models, the investigators found that inflammatory cell trafficking between a hematopoietic organs and sites of tissue injury is controlled by CXCL12 and its receptor CXC receptor 4. And bolus injectives of a highly selected peptidic macrocycles CXC receptor 4 antagonist, enhanced tissue repair and functional recovery after re-perfused acute myocardial infarction in mice. And interestingly, the therapeutic effects require a dendritic cell priming and we're specifically mediated by t-regulator cells. Intermittent CXC R4 blockade mobilized the t-regulator cells from their splenic reservoir. Leading to their enhanced recruitment to the infarct region. Dr Carolyn Lam:                So bring it home for us, Greg. What does this mean clinically for MI management in humans? Dr Greg Hundley:             Right. Highlighting the translational potential. What we might infer is that CXC receptor 4 blockade reduces infarct volume and improved systolic function in a porcine close chest model of re-perfuse acute myocardial infarction.                                                 And so, the results of both the mouse experiments and this sort of translational model in pigs should stimulate further research into therapeutic potential of CXC R4 blockade after MI and in other acute conditions were excessive, innate or adaptive immune responses cause immunopathology. Dr Carolyn Lam:                Fascinating. So from one preclinical paper to another, but this time focused on heart failure. And focus specifically on titin. Titin is this giant elastic protein that spans the half-sarcomere from the Z-disk to the M band, and it acts like a molecular spring and a mechanosensor that has been linked to striated muscle disease. Now the pathways that govern tight independent cardiac growth and contribute to disease are diverse and have been really difficult to dissect. And so corresponding author Dr Gotthardt, from Max Delbruck Center for Molecular Medicine and the German Center for Cardiovascular Research and his colleagues aimed to study titin deficiency versus titin dysfunction.                                                 And how they did that is they generated and compared striatum muscles specific knockouts with progressive postnatal loss of the complete titin protein. And that's by removing Exxon 2. Or an M-band truncation that eliminates the proper structure and integration, but retains all the other functional domains. So they then evaluated cardiac function, cardiomyocytes mechanics, and the molecular basis of the phenotype. Now, what they found was that progressive depletion of titin led to sarcomere disassembly an atrophy in striated muscle. And in the complete knockout, remaining titin molecules had increased strain resulting in mechanically induce trophic signaling and eventual dilated cardiomyopathy.                                                 On the other hand, the truncated titin helped maintain passive properties and thus reduced mechanically and do signaling. In other words, truncations versus loss of titin, differentially affected cardiac pathology with atrophy versus dilated cardiomyopathy respectively. And together, these findings really contribute to the molecular understanding of why titin mutations differentially affect cardiac growth and have implications importantly for genotype, phenotype relations that support a personalized approach to the diverse titinopathy. Dr Greg Hundley:             Interesting, Carolyn. All this information on titin. So why is it clinically important? Dr Carolyn Lam:                Well, first of all, tightened mutations are the most common genetic basis of heart disease and the findings are clinically relevant, as I said, for understanding the genotype phenotype relations at the Titin mutation. But understanding the integration of Titin based signaling and sarcomere biology could indeed help personalize diagnostics by improved clinical decisions and maybe identify suitable therapeutic targets for these titinopathy. But that of course requires much further work. Well that brings us to the end of our summaries. Let's go to our feature discussion.  Dr Greg Hundley:            Welcome everyone to our second segment of our program. We're discussing an interesting paper today entitled Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy. And we want to welcome our coauthors Elijah Behr and Mary Sheppard from St George's University in London. And also, our own associate editor, Sami Viskin to discuss this paper. Mary, can you tell us a little bit about your study design here, the population and the hypothesis and some of your results? Dr Mary Sheppard:          I am a cardiac pathologist of 20 years and I have a special interest in sudden death. Over this time, I've established a national pathology database, where pathologists throughout the country when they have a sudden death, which is likely cardiac and non-ischemic, they will send the heart or tissue blocks insides to me for my opinion concerning the death. We have as a result developed a large number, over 5200 cases which has now built up to 6000. It's the largest pathological series in the world.                                                 And I was also discovering the pathologists were either under or over diagnosing all types of cardiomyopathy but particularly ergogenic cardiomyopathy. And that is why with Chris Miles, our research fellow, we looked in detail at what I had diagnosed, or the pathologist as ergogenic cardiomyopathy and we actually honed are pathological diagnostic criteria for this very important entity. Establishing that left ventricular is five and ventricular and left and ventricular is the norm almost. That right or left ventricular is unusual by themselves and even in 20%, one in five, the heart can look macroscopically normal. So that histology is essential when you're making this diagnosis. You cannot make the diagnosis pathologically without histologically examining the heart. Dr Greg Hundley:             Very good, Mary. And did you also examine some genetic markers in some of the subsets of the patients? And how did you decide who those individuals would be that received the genetic analysis? Dr Mary Sheppard:          A small subset and I will hand over to Elijah Behr, my colleague concerning that. Dr Elijah Behr:                   The genetic tissue is only available in a minority of cases. We've developed a pipeline now with the referring pathologists who are increasingly they're sending samples of spleen suitable for DNA extraction that allow us then to do a retrospective postmortem genetic testing or molecular autopsy. But unfortunately, in this particular series we only had a small proportion. I think there were roughly about 24 out of the 202 cases, so just over ten percent. And interestingly, while we didn't necessarily mirror the expected yield of genetic testing that is seen in clinical cases, where you may see about 40% carrying pathogenic variance. We certainly picked up some important pathogenic variance, particularly those that are often associated with highly penetrant and more severe disease. In particular TMEM43 and desmoplakin. These findings may reflect the small size of the sample, but it also may reflect where the greatest risk for sudden death from ergogenic cardiomyopathy lies. Dr Greg Hundley:             Elijah, getting back to some of the patients that experienced the sudden death in the study population Mary was referring to, were there characteristics that were associated with the sudden death? For example, those that might be related to gender or activity? Dr Elijah Behr:                   So the majority of the cases were male. The majority has never had prior symptoms. These were unheralded deaths. The majority did not have a family history and I think the majority were addressed, but those that were athletes, we're much more likely to have died during exertion. So as we found with ergogenic cardiomyopathy in general and exertion is a trigger to sudden death. The risk was higher and compared to the athletes in death during exertion was associated with being younger as well. I think exertion and sports clearly play a role in ergogenic cardiomyopathy. It didn't appear to play a role in whether there was left ventricular involvement or not, but certainly a role at more severe presentation.  Dr Greg Hundley:            Maybe both Mary and Elijah answering this. You found histopathological evidence of fibrosis and fatty infiltration. How extensive was that? And do you think that could be identified with a test like maybe magnetic resonance imaging? Dr Mary Sheppard:          Yes. Our diagnostic criteria which is illustrated in the addendum is that it was at least two blocks of tissue. We always look at 10 to 12 to 15 blocks of tissue from both right and left ventricle. And at least two of the blocks had to have fibrosis with fat in 20% of the area examined. We did not include inflammation because inflammation is, an important histological criterion in our experience. We were very precise about that because you need that much at least to make the diagnosis. A little bit of fibrosis or a little bit of fat is not sufficient by itself. Dr Greg Hundley:             When you mention a block, for us clinically, how much myocardium would that be? For example, on an imaging test like an echo or an MRI scan. Dr Mary Sheppard:          One to two centimeters squared. Dr Greg Hundley:             So quite a bit. Dr Elijah Behr:                   You're looking at probably around two to four millimeters of potential depth of fibrosis. And what we've seen clinically in LV involvement of MRI scans is miss two epicardial late enhancement. Now the question is whether our scans are sensitive enough to pick that up? Given the technology available or a sense to the histopathology and I think that's why maybe some of the clinical studies have tended to miss the true proportion of left ventricular involvement. Because of the relative subtlety of the fibrosis compared to the technological ability to discriminate it. I mean certainly when you look at our cases that were diagnosed previously with cardiomyopathy, either they were arrhythmogenic or dilated, many did have imaging findings if MRI was performed, that would indicate or suggest some left ventricular involvement. But as you know, the task force criteria for arrhythmogenic cardiomyopathy having very much right ventricular focus. An LV imaging findings and LV ECG findings are just not part of those at the moment. Dr Greg Hundley:             Was there a particular location within the heart where there was a predilection toward the findings of fibrosis and fat? Dr Mary Sheppard:          In the posterior basal wall particularly, transmural involves going from the epicardium to the sub endocardium and also the interior walls of the left ventricular were the predilection areas. Dr Elijah Behr:                   I think that's what we see on our MRI scans as well. When you look at these patients, that posterior basal area, is the one that tends to light up the most. Dr Mary Sheppard:          It is believed that increased stress in that area gives more damage because of the stretching away from the septum. Dr Greg Hundley:             Very interesting. So Elijah, you had mentioned task force criteria. I want to shift to Sami now and ask, Sami, can you help us put this in perspective relative to the existing task force criteria and then the findings in this study? And how that could lead to subsequent changes down the road?  Dr Sami Viskin:                 Okay, so it is difficult to place this in the context of the task force because mentioned by Elijah, the taskforce are focused on a disease that is believed to be in the right ventricle. And the study shows that many of the sudden death cases will involve the left ventricle. One of the most important messages of this paper is importance of her forensic examination. And importance of making it for anything examination in the center of expertise. We know of patients that will travel a thousand miles to undergo surgery or an ablation procedure, but families do not think that way when there is casualty or family dies. You may take a postmortem as a given, but in many countries, including my own, most cases of sudden death would not be followed by a post mortem and will not go into center of expertise. And you cannot overemphasize the importance of doing that because then you have to know what you are looking for in the remaining relatives is extremely important. Dr Greg Hundley:             Very good. How about from the perspective as an electrophysiologist? Does this impact in any way how you might evaluate a younger person with syncope? Dr Sami Viskin:                  Well, it is difficult to conclude from this paper about how to evaluate patients with syncope because most of the cases in this series don't have symptoms at all. But this paper calls to very interesting investigations by Mario del Mar and others in New York. Looking about the electrophysiology consequences of a disease like right ventricle are like a bit mechanical in [inaudible 00:21:58] The tissues becomes editing the disease, the electrical properties how the patients in brugada can cause malfunction of this sodium channel and create a disease that is more like brugada and dysplasia at the beginning. So, the entire correlation between a morphologic disease and the metrical disease and we used to think they are two different things. And now we see that we can actually put them together and you can go through stages where one disease is before an electrical disease and only at later stages it becomes a morphological evident disease.  Dr Greg Hundley:            A fantastic discussion on pathologic findings. Sami making the point that certainly in cases for young individuals having a postmortem examination performed at centers that have expertise such as what Mary's described, can be very important. And then Elijah, helping us to understand with arrhythmogenic cardiomyopathy, number one, findings are not, we shouldn't just be thinking about the right ventricle in isolation, but also the left ventricle. Fibro fatty infiltration, particularly in the posterior basal wall could be an important thing to look for, for those that are performing the magnetic resonance imaging exams. And then lastly, many of the patients in the study like this, the first presentation was of sudden death. And we need to be cognizant that this condition could be prevalent in the population and not necessarily appreciated by some of our current task force guidelines and examinations. So, what an outstanding discussion. And I think for today, we want to thank our authors and our associate editor and wish everyone a great week.                                                 On behalf of Carolyn and myself, we look forward to seeing you next week. Thank you very much. Dr Carolyn Lam:                This program is copyright American Heart Association 2019.  

Editor's Summary by Howard Bauchner, MD, Editor in Chief of JAMA, the Journal of the American Medical Association, for the December 11, 2018 issue

In this episode, we dive in to titin's role in muscle contraction, followed by an interview with University of Calgary's Professor Walter Herzog who talks about the role of nutrition in osteoarthritis development, who he looked up to as a student in biomechanics, and more. Followed with research fails!

In this episode, we dive in to titin's role in muscle contraction, followed by an interview with University of Calgary's Professor Walter Herzog who talks about the role of nutrition in osteoarthritis development, who he looked up to as a student in biomechanics, and more. Followed with research fails!

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.                                                 Ticagrelor has shown superior efficacy to clopidogrel in the management of acute coronary syndromes. But what about in patients undergoing PCI for stable coronary artery disease? Well, our feature paper this week gives us answers to this question but you're going to have to wait to the feature discussion to hear these answers. That's coming up right after these summaries.                                                 Our first original paper this week shows that RBM20 mutation carriers have an increased risk of arrhythmias. You may recognize RBM20 as that splicing factor which targets multiple pivotal cardiac genes such as Titin and Calcium/Calmodulin-Dependent Kinase 2 Delta or CAMK2D. In today's paper first author Dr van den Hoogenhof and co-corresponding authors Dr Pinto and Creemers from Academic Medical Center Amsterdam, compared the clinical characteristics of RBM20 and Titin mutation carriers and used RBM20 knock out mice to investigate the downstream effects of RBM20 dependent splicing. They showed that loss of RBM20 disturbed calcium handling and led to more pro-arrhythmic calcium releases from the sarcoplasmic reticulum. Patients that carried a pathogenic RBM20 mutation had more ventricular arrhythmias despite a similarly depressed left ventricular function compared to patients with a Titin mutation.                                                 Targets of RBM20 splicing were enriched for calcium and ion handling genes, most notably CAMK2D and type 2 Ryanodine receptor. Loss of RMB20 induced an increased L-Type Calcium current density, intracellular calcium overload, increased sarcoplasmic reticulum calcium content and increased spontaneous calcium releases which all could be attenuated with treatment with an L-type calcium channel blocker. Furthermore, these results suggest that RBM20 mutation carriers should be closely monitored for potential electrical disturbances and cardiac arrhythmias even in the early stages of disease.                                                 Echocardiographic quantitation of degenerated mitral regurgitation is recommended in clinical guidelines but is it really scalable to routine clinical practice? First author Antoine, corresponding author Sorano from Mayo Clinic Rochester Minnesota and their colleagues looked at more than 3900 patients diagnosed with isolated mitral valve prolapse between 2003 and 2011 and to any degree of mitral regurgitation quantified by any physician or sonographer in routine clinical practice. They found that in multi-variable analysis routinely measured effective regurgitant orifice area was associated with mortality independent of left ventricular ejection fraction and systolic diameter symptoms or age and comorbidities. Furthermore, compared with general population mortality excess mortality appeared for moderate mitral regurgitation with an effective regurgitant orifice area above 20 squared millimeters and became notable with an effective regurgitant orifice area above 30 squared millimeters which then steadily increased with even higher levels of above 40. Thus, quantitation of degenerative mitral regurgitation is scalable to routine clinical practice with strong independent prognostic power when performed routinely by multiple practitioners.                                                 The next study identifies a novel mechanism of lipid homeostasis that is linked to a pseudo gene associated with the recently discovered apolipoprotein known as APOO. Co-first authors Montasser and O'Hare, corresponding author Dr Mitchell from University of Maryland School of Medicine in Baltimore, performed an array based association analysis in more than 1100 Amish subjects and identified a variant strongly associated with LDL cholesterol levels. They identified a founder haplotype on chromosome 5 which was associated with a 15 mg/dl increase in LDL cholesterol after recombination mapping, the associated region contained eight candidate genes. Using a zebra fish model to evaluate the relevance of these genes to cholesterol metabolism they found that the expression of the transcribed pseudo gene APOOP1 increased LDL cholesterol and vascular plaque formation. Thus, based on these data the authors proposed that APOOP1  regulates levels of LDL cholesterol in humans and represents a novel mechanism of lipid homeostasis.                                                 The Orion-1 trial demonstrated that inclisiran which is a small interfering RNA therapeutic that targets PCSK9 MRNA with [inaudible 00:05:42] produces significant LDL reduction. In today's study from Dr Ray from Imperial College London and colleagues, the authors described in detail the effect of inclisiran on prespecified secondary lipid and lipoprotein outcomes over time for up to 210 days and also described the individual variation and response in these measures. They found that a single 300 milligram dose of inclisiran  lowered non-HDL cholesterol at day 180 by 35% and a second dose at day 90 resulted in a 46% reduction at day 180. Similarly a single dose of 300 milligrams of inclisiran  reduced apolipoprotein B by 31% at day 180 and a second dose of 300 milligrams administered in day 90 reduced apolipoprotein B by 41%. Significant reductions in all atherogenic lipoproteins measured were sustained through today 210. Furthermore, every individual had a reduction of apolipoprotein B and non-HDL cholesterol at 180 days with the 300 milligram two-dose regimen of inclisiran. Thus, inhibiting the synthesis of PCSK9 through small interfering RNA may be a viable alternative to monoclonal antibodies with respect to effects on atherogenic lipoproteins and that brings us to the end of our summaries. Now for our feature discussion.                                                 Ticagrelor has superior efficacy to clopidogrel in the management of acute coronary syndrome but it has not really been assessed in patients undergoing PCI for stable coronary artery disease. For our feature paper today it's going to shed some light and help us with this question and these are the results of the STEEL-PC trial. I'm so pleased to have with me right now the corresponding author Dr Robert Storey from University of Sheffield in the UK as well as our associate editor who managed this none other than Dr Stefan James from Uppsala University. Thank you.                                                 Rob, could you tell us what is the issue you tried to address and because your study is not that simple, we're not used to thinking about these pharmacodynamic and kinetic studies so could you explain a bit of what you did? Rob Storey:                        Well it's quite a few concepts that we assessed in this study. We've got data from a number of studies showing that Ticagrelor both at doses of 90 mg twice daily and 60 mg twice daily is more reliable and superior P2Y12 inhibitor compared to clopidogrel. We've got this issue of very variable response to clopidogrel with some poor responders and some high responders and a range in between. That's fairly well established and part of this study was to get more data on the 60 mg dose of Ticagrelor in these stable CAD patients undergoing PCI and get some pilot data on clinical efficacy obviously this study was not part of clinical outcomes.                                                 But, there's another issue in terms of adenosine uptake so Ticagrelor has a relatively weak effect on adenosine uptake into red cells and other cells and this may or may not explain some of its clinical effects including some adverse effects such as dyspnea. We wanted to get a better idea of the impact of Ticagrelor at both these doses on adenosine uptake. Dr Carolyn Lam:                Could I ask ... Okay this may be naïve. I'm not an interventional cardiologist but why would you expect something different in an acute coronary syndrome compared to stable coronary artery disease? Is there an underlying hypothesis there? Rob Storey:                        Well there can be changes to their differences in platelet reactivity although those aren't particularly great and overwhelmed really by P2Y12 inhibitor like Ticagrelor which gives such reliable inhibition of the P2Y12 receptor. But, there have been a limited number of groups that have looked at adenosine uptake and so we wanted to get independent confirmation or not of whether Ticagrelor therapeutic concentrations impacting on adenosine uptake and get some ideas of whether it's affecting circulating adenosine levels. That's an important question in terms of understanding the mechanisms and actions of Ticagrelor. Dr Carolyn Lam:                Got it. Thanks for breaking it down so nicely. So what did you find? Rob Storey:                        What we found was surprisingly that we saw no impact of Ticagrelor at either dose and at any time point within a month after PCI on adenosine uptake. That is the circulating levels of adenosine and the rate at which adenosine is taken up by cells in the blood mainly red blood cells. The explanation for that really is that the therapeutic levels of Ticagrelor that you see are not sufficient to impact on adenosine uptake because it's a very weak inhibitor of the adenosine uptake pathway known as the MT1. The therapeutic levels are just not getting up to a high enough concentration to have a significant impact on that. Dr Carolyn Lam:                Stefan, you've thought a lot about this. What did you think of the findings? Stefan James:                    I think it's very interesting. Of course, the pharmacodynamic effects that you can measure by pretty simple means, the level of platelet inhibition, it should be similar in ACS and stable coronary artery disease and I think it's sort of confirming what Rob has been showing in other populations with ACS ... we have been very interested in trying to understand the additional mechanisms of action of Ticagrelor... try to understand the mortality rate without the benefit for Plato, for example. Was it only -- platelet  inhibition or were there other mechanisms? And, there is a specific Ticagrelor related side effect, dyspnea, which we would have been interested in understanding... is this a  mechanism of action? We can't really explain that.  There are other mechanisms and other effects that we have seen can also be explained by adenosine, so I thought it was very interesting and important to understand more about these mechanisms.   Dr Carolyn Lam:                Yeah. Stefan James:                    But I would like to ask you, Rob. Do you think this adenosine hypothesis now, is dead, or should we still try to explore this? Rob Storey:                        Well of course in this study what we didn't look at was the adenosine kinetics in the tissue level which is where we hypothesize the dyspnea may arise from stimulation of C5 is in the lung tissue so we're missing that piece of information. It's still conceivable that very weak levels of ENT-1 inhibition may impact from adenosine levels in the tissue. We're not seeing a strong ENT-1 inhibition sufficient to raise circulating levels or something that we can pick up on this in vitro assay.                                                 I think it still remains an open question. We've got this sort of contradictory information from drugs like cangrelor and other drugs in development like Elinogrel  where we don't see an impact on adenosine but they still may cause dyspnea.  So I think it's a very open question still. Stefan James:                    Do you think that your paper gives us additional strength to the hypothesis that the mortality benefit for ticagrelor as seen in Plato is explained by the platelet inhibition and the balance between the reduction in ... Rob Storey:                        Well I think what we see really in all these studies is that Ticagrelor is a fantastically effective PTY12 inhibitor. It gives you the best level of platelet inhibition during maintenance therapy out of all the available PTY12 inhibitors. And clearly having such more reliable PTY12 inhibition than clopidogrel could still be driving a mortality benefit in high risk patients so we can't exclude the adenosine pathway contributing to some of the clinical effects but I think this sways me a little bit more to the position of thinking this is most of the benefits through platelet inhibition. Dr Carolyn Lam:                Interesting. So you're on the cutting edge of this. What's the next step then? Rob Storey:                        Clearly we can see that very effective and reliable P2Y12 inhibition is important and leads to clinical benefits and I think we need to implement that wherever we're using P2Y12 inhibitors. We need to take that message and use a more consistent therapy rather among those with associated with variable response which doesn't seem to make sense. I think this stable PCI population, their risk has fallen. And we see that in this study, quite a number of patients report a response to clopidogrel but no stent thrombosis.                                                 That really reflects, I think improvements in stent design and implantation techniques, so the implication is that maybe aspirin alone is enough to prevent stent thrombosis with modern techniques if you get a good result but in the higher risk patients particularly the ACS patients it's likely you need much more reliable platelet inhibition and that's why Ticagrelor really provides this security. Dr Carolyn Lam:                So, Rob there is one thing you tested two doses and they seemed to be equivalent at least in antiplatelet inhibition, right? So what does this mean? Should we maybe preferentially use the lower dose from now on, is there still room for the higher dose? Could you share some insights there? Rob Storey:                        Well I think one has to be cautious in not jumping to adopt a dose just on the basis of pharmacodynamic data but clearly what we show is that the 60 mg dose of Ticagrelor offers a very reliable and consistent level of PTY12 inhibition and that's likely to be very effective in preventing stent thrombosis in combination with aspirin. We also show signals that were also shown in the Pegasus study that the 60 mg dose may be better tolerated such as with lower levels of dyspnea.                                                 So, there is the option for off label use of the lower dose of Ticagrelor in those who cannot tolerate the high dose due to dyspnea because certainly they'll have better platelet inhibition down titrating from 90 to 60 and if they were to switch to Clopidogrel. So I think our study offers some comfort in terms of that aspect. The only caveat is that you have to be careful not to use strong CYP3A inducers such as some epilepsy drugs with Ticagrelor cause that can increase the metabolism and we did have one case of high platelet reactivity with strong CYP3A inducers so using a higher dose initially I think is a good idea. The label says 90 mg for 1 year following ACS and the 6 is licensed beyond one year as a down titration predominantly.                                                 Our study certainly gives some comfort that down titrating earlier if a patient can't tolerate the 90 for whatever reason, seems to be a justifiable thing. And the other thing is the European guidelines support the use of Ticagrelor off label in elective PCI and our study certainly gives some comfort that off label use and the low risk elective PCI patients of the 60 mg dose can be justified at least from a pharmacodynamic point of view. Dr Carolyn Lam:                Well, thank you because that's exactly what our audience is loving to hear. How do these findings translate into the clinical practice - Would you have any other take home messages for the clinicians listening in? Rob Storey:                        Well I think one thing we looked at also was troponin release which is very common after PCI. We didn't see an impact of PTY12 inhibition high levels on troponin  release and I think that sort of caveat in terms of that's not going to be the best measure in terms of surrogate for efficacy in the PCI population. The other question really is, how much of the platelet inhibition and how much of the adenosine effects of Ticagrelor influence the clinical outcomes and clearly the studies sways towards the platelet inhibition very consistent high level of platelet inhibition explaining most of the benefits. Carolyn Lam:                      You've been listening to circulation on the run, don't forget to tune in again next week.  

Jane Ferguson: Hello. Welcome to episode 19 of Getting Personal: Omics of the Heart, the issue from August 2018. I am Jane Ferguson, and this podcast is brought to you by the Circulation: Genomic and Precision Medicine Journal and the American Heart Association Council on Genomic and Precision Medicine. Before I dive into the papers from this month, a reminder that early bird registration for AHA Scientific Sessions runs until September 4th, so go register now if you haven't already to take advantage of reduced rates. The meeting will be held in Chicago from November 10th through 12th, and it's the first year of the new three-day meeting format. It's already promising to be a really great meeting, and I'm hoping to see a lot of you there.     The August issue has a number of really interesting papers. First up, Gardar Sveinbjornsson, Eva Olafsdottir, Kari Stefansson, and colleagues from deCODE genetics-Amgen report that variants in NKX2-5 and FLNC cause dilated cardiomyopathy and sudden cardiac death. This team leveraged available DNA samples from the Icelandic population to carry out a genome-wide association study in 424 cases of dilated cardiomyopathy and over 337,000 controls. They applied whole genome sequencing to all of these samples, allowing them to identify common and rare variants. In total, they tested over 32 million variants.     They found two variants that were significantly associated with DCM at genome-wide significance, a missense variant in NKX2-5 and a frameshift in FLNC, both associated with heart failure and sudden cardiac death. Further, the NKX2-5 variant was associated with atrioventricular block and atrial septal defect. Although these variants are rare and not documented in other populations, they are significant contributors to familial DCM in Iceland. Because of the unique population structure of Iceland and known genealogy, the researchers were able to trace the NKX2-5 variant back to a common ancestor born in 1865. They traced the FLNC variants to a common ancestor born in 1595.     While the specific variants identified in this study may not be present in other populations, they are located in genes with known relevance for cardiac function. NKX2-5 encodes a cardiac transcription factor, which is required for embryonic cardiac development, and other variants in this gene have been associated with cardiac dysfunction in other populations. FLNC encodes filamin-C, a muscle cross-linking protein. Variants in FLNC have previously been ascribed to associate with myofibrillar myopathy, muscular dystrophy, and cardiomyopathy. This study adds to our knowledge of the genetics of dilated cardiomyopathy and supports screening for NKX2-5 and FLNC variants, particularly in the Icelandic population, which would allow for early intervention and monitoring in carriers.     Staying with the topic of dilated cardiomyopathy, Inken Huttner, Louis Wang, Diane Fatkin, and colleagues from the Victor Chang Cardiac Research Institute in Australia report that an A-band titin truncation in zebrafish causes dilated cardiomyopathy and hemodynamic stress intolerance. We actually talked to Dr. Wang about this research last year when he was presenting this as a finalist for the FGTB Young Investigator Award. You can go back in the archives to episode 10 from November 2017 if you'd like to hear more.     Titin mutations are responsible for a large number of cases of dilated cardiomyopathy, but there are also individuals with titin mutations that remain asymptomatic. This group used zebrafish as a model of human titin mutations and generated fish with a truncating variant in the A-band of titin, as has been identified in families with DCM. They found that homozygous mutants had a severe cardiac phenotype with premature death, but that heterozygous carriers survived into adulthood and developed spontaneous DCM. Prior to onset of DCM, the heterozygous fish had reduced baseline ventricular systolic function and reduced contractile response to hemodynamic stress, as well as ventricular diastolic dysfunction.     Overall, the mutant fish displayed impaired ability to mount stress responses, which may have contributed to development of disease. Extrapolating this to humans, this could suggest that hemodynamic stress may be a factor that contributes to timing and severity of disease in individuals with titin variants. Hemodynamic stress can be exerted by exercise, pregnancy, and other diseases contributing to ventricular volume overload. Modifying these hemodynamic stressors in at-risk subjects could potentially help to modulate the severity of DCM phenotypes.     Moving on to the topic of coronary artery disease, Vinicius Tragante, Daiane Hemerich, Folkert Asselbergs, and colleagues from University Medical Center Utrecht in the Netherlands report on druggability of coronary artery disease risk loci. This group was interested in using results from genome-wide association studies for CAD to identify new targets that may be amenable for drug repurposing. They used results from published GWAS for CAD and created a pipeline to integrate these loci with data on drug-gene interactions, chemical interactions, and potential side effects. They also calculated a druggability score based on the gene products to prioritize targets that are accessible and localized to increase the chance of a drug being able to find the target without affecting core systemic processes or housekeeping genes.     Their pipelines allowed them to identify three possible drug-gene pairs, including pentolinium to target CHRNB4, adenosine triphosphate to target ACSS2, and riociguat to target GUCY1A3. They also identified three proteins to be prioritized for drug development, including leiomodin 1, huntingtin-interacting protein 1, and protein phosphatase 2, regulatory subunit b-double prime, alpha). While these predictions were all made in silico and need to be extensively tested in clinical trials, the pipeline did identify many current therapies for CAD and myocardial infarction, including statins, PCSK9 inhibitors, and angiotensin II receptor blockers. These positive controls support that this method can successfully discover effective CAD therapies.     Staying on the topic of drugs, Kishan Parikh, Michael Bristow, and colleagues from Duke University report on dose response of beta-blockers in adrenergic receptor polymorphism genotypes. Two clinical trials have reported pharmacogenomic interactions between beta-blockers and beta-1 adrenergic receptor genotype in the setting of heart failure with reduced ejection fraction. In a retrospective analysis in almost 2,000 subjects from the BEST and HF-ACTION studies, the authors analyzed whether genotype at the Arg389Gly polymorphism in beta-1 adrenergic receptor, or an indel in the alpha-2C adrenergic receptor interacted with drug dose to affect mortality and hospitalization.     They found that ADRB1 genotype affected mortality in response to drug dose with less all-cause mortality in high versus no or low-dose beta-blockers in individuals homozygous for arginine at position 389, but not in individuals carrying a glycine at that position. In individuals on high-dose beta-blockers, genotype did not affect outcomes, but there was a significant difference by genotype in all-cause mortality in individuals on no or low-dose beta-blockers. These data support the guideline recommendations to use high-target doses of beta-blockers in HFrEF.     Switching gears towards precision medicine and genotype-guided approaches, Laney Jones, Michael Murray, and colleagues from Geisinger were interested in the patient's perspective. In their paper, Healthcare Utilization and Patients’ Perspectives After Receiving a Positive Genetic Test for Familial Hypercholesterolemia, they explored the impact of providing genotype test results for familial hypercholesterolemia to subjects participating in the MyCode Community Health Initiative. In MyCode, exome sequencing is conducted in participants, and results are returned for pathogenic and likely pathogenic variants in genes representing actionable conditions based on American College of Medical Genetics secondary findings and recommendations.     It is estimated that 3.5% of MyCode participants will be carriers of such variants, and this number may increase as more variants are discovered. In this pilot study, the authors screened for individuals with mutations in LDLR, APOB, or PCSK9, consistent with FH. They identified 28 individuals, of which 23 were eligible for inclusion in the study. Only five of the 23 subjects had previously been diagnosed with FH. Receipt of genetic test results led to change in medications in 39% of individuals. 96% of the subjects had previous LDL measurements, but only four subjects had ever met LDL goals. After genetic test results, three individuals met their LDL goals.     Seven individuals consented to participate in interviews about their experience. Almost all of these subjects already had a personal or family history of high cholesterol or heart disease, and all subjects felt that they were being adequately treated. Only three of the seven subjects mentioned using diet and exercise to control their high cholesterol, with most individuals being relatively unconcerned because they felt their medication was effective in controlling disease risk.     While the numbers studied here are too small for any statistical testing or inference, the paper describes the results from the interviews, including some excerpts from patients, which really highlight the complexities of returning results and of helping patients understand what their results mean. Given increasing genetic testing and returning of results, studies like this are really important to help us figure out the most effective ways to communicate results and support patients and their care providers.     Also from a patient-centric perspective, we have an article from Susan Christian, Joseph Atallah, and colleagues from the University of Alberta in Canada on when to offer predictive genetic testing to children at risk of an inherited arrhythmia or cardiomyopathy, the family perspective. This article considers the timing of cascade testing to predict inherited arrhythmias and cardiomyopathy in children of affected individuals. European and North American guidelines differ on when or if they recommend genetic testing in children.     In this study, surveys were circulated to foundations and patient groups to solicit familial perspectives on when genetic testing should be offered to children. In total, 213 individuals responded. In the case of long QT syndrome, 92% of respondents thought testing should be offered before the age of five, while 77% of respondents thought genetic testing should be offered before the age of 10 for hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy.     Overall, the potential benefits of genetic testing, including guiding therapies, sport participation, and decreasing worry were ranked more highly than potential risks of discrimination or increasing worry that could occur from genetic testing. Overall, the responses indicated that families would welcome the option of genetic testing for at-risk children from a young age and support initiating early discussions with families to explore costs and benefits of early genetic testing.     Finally in this issue, we have a review from Paul Franks and Nicholas Timpson from Lund University and the University of Bristol entitled Genotype-Based Recall in Complex Cardiometabolic Traits. This review looks at the increasing practice of selecting samples or individuals from larger cohorts or biobanks based on their genotype to carry out additional studies. The article focuses on examples of such genotype-based recall studies in cardiometabolic disease, highlights approaches and new methods, and discusses the ways these types of studies can be used to extend and supplement randomized trials and large population-based studies.     As always, you can find all the articles, accompanying editorials, and video summaries online. Our website recently underwent some redesigns and has moved. You should be redirected if you have the older site bookmarked, but you can also find us directly at ahajournals.org/journal/circgen. Also, thanks to everyone who participated in the Twitter poll last month. You were pretty evenly split on what you want to hear in the podcast, but please continue to leave suggestions and feedback on what we're doing and where we can improve things. That's it for the August issue of Circulation: Genomic and Precision Medicine. Thanks for listening, and tune in next month for more.    

Undefeated Bellator star and model, Anastasia Yankova, joins the guys in studio to talk about everything. Her training camp at AKA Thailand, her life before fighting, since starting her fight career, her past health issues, her artwork, and why she quit drinking alcohol after she was 5 years old. Also, some rare bonus sparring clips of her training with BAMMA World Flyweight Champion Daniel Barez and Titin, as she prepares for Bellator 200 this May. This is Anastasia's very first public conversation in English, and really gives an inside look of one of the most popular and mysterious figures in the sport. Watch The Taping Of This Episode On Youtube: https://www.youtube.com/watch?v=OWDoBRcLTkM Its a must see! Business E-mail: Info@MikeSwick.com Anastasia Yankova: http://www.Instagram.com/Anastasia_Yankova http://www.twitter.com/YankovaAn http://www.Facebook.com/AnastasiaYankovaOfficial (NEW) Mike Swick: http://www.Instagram.com/Mike_Swick http://www.twitter.com/OfficialSwick http://www.Facebook.com/MikeSwick Marc Bogutzki: http://www.Instagram.com/MarcBogutzki Mike Swick is a 15 time UFC veteran and former top contender in two different weight classes. He is also the founder and CEO of the AKA Thailand super gym in Phuket, as well as owner of MikeSwick.com, and one of northern California's largest print shops, Spartan Screen Printing. Marc Bogutzki is Mike's longtime friend and has been by his side since high school. Known as one of the funniest guys that's never took stage, he is also the complete opposite of Mike. Marc has never been in a fight in his entire life, and doesn't live near what you would consider a healthy lifestyle. This is why at 50,000 subscribers on our YouTube channel, Marc has vowed to train and take a real Muay Thai fight in a stadium in Thailand. Follow Us: http://www.youtube.com/c/RealQuickwMikeSwickPodcast http://itunes.apple.com/us/podcast/real-quick-w-mike-swick-podcast/id1268441670 http://soundcloud.com/RealQuickPodcast http://Instagram.com/RealQuickWithMikeSwick http://Twitter.com/RQMSPodcast Host: Mike Swick Co-Host: Marc Bogutzki Guest: Anastasia Yankova Produced & Directed by: Mike Swick Music Producer: Benny Youngbaht Music: Danny Bunnathong Artwork: Simon Netherton For more info about the show, Mike, and all things fight related, check out the #1 fight entertainment website: http://www.MikeSwick.com For more info about AKA Thailand: http://AKAThailand.com http://Facebook.com/AKAThailandGym http://Instagram.com/AKAThailand http://Twitter.com/AKAThailand Thank you for listening!

Dr. Paul Wang:           Welcome to the monthly podcast On the Beat for Circulation Arrhythmia and Electrophysiology. I'm Dr Paul Wang, editor-in-chief, with some of the key highlights for this month's issue. We'll also hear from Dr. Suraj Kapa reporting on new research from the latest journal articles in the field.                                                 In our first article, Barry Maron associates report on the long term clinical course of hypertrophic cardiomyopathy patients following ICD therapy for ventricular arrhythmias. They studied a cohort of 486 high-risk hypertrophic cardiomyopathy patients with ICDs from eight international centers. Of these 486 patients over 6.4 years, 94 patients or 19% experienced appropriate ICD interventions, terminating VT or VF. Of the 94 patients receiving appropriate ICD therapy, 87 were asymptomatic or only mildly symptomatic at the time of appropriate ICD interventions. Of these 87 patients, 74 or 85% remained in classes one or two without significant change in clinical status of the subsequent 5.9 years up to 22 years. Among the 94 patients, there was one sudden death in three patients who died from non arrhythmic hypertrophic cardiomyopathy related processes. Post ICD intervention, freedom from hypertrophic cardiomyopathy, mortality was 100% at one year, 97% at five years, and 92% at 10 years, distinctly lower than the risk of ischemic or non ischemic cardiomyopathy in ICD trials.                                                 Hypertrophic cardiomyopathy patients with ICDs interventions reported the heightened anxiety and expectation of future shocks. However, they did not affect general psychological well-being or quality of life. The authors concluded that in hypertrophic cardiomyopathy, unlike ischemic heart disease, prevention of sudden death with ICD therapies unassociated with a significant increase in cardiovascular morbidity and mortality, nor transformation into heart failure deterioration, ICD therapy does not substantially impair overall psychological and physical well-being. In our next article, Abdulla Damluji and associates examined the cost of hospitalizations for cardiac arrest using the US nationwide inpatient sample from 2003 to 2012. Using the log transformation of inflation adjusted costs the authors examined 1,387,396 patients who were hospitalized after cardiac arrest. They had a mean age of 66 years. Inpatient procedures included coronary angiography in 15%, PCI in 7%, intra-aortic balloon pump in 4.4%, therapeutic hypothermia in 1.1%, and mechanical circulatory support in 0.1% of patients.                                                 Notably the rates of therapeutic hypothermia increased from 0 in 2003 to 2.7 in 2012, p less than 0.001. Both hospital charges inflation adjusted costs linear increased over time. In a multi-variant analysis predictors of inflation adjusted costs included large hospitals size, urban teaching hospital, and length of stay. Among co-morbidities, atrial fibrillation or fluid and electrolytes imbalance were the most common associated with cost. The authors found that during the period between 2003 and 2012 post cardiac arrest, hospitalizations had a steady rise and associated healthcare costs likely related to increase length of stay, medical procedures and systems of care.                                                 In our next paper, Peter Huntjens and associates examined intrinsic interventricular dyssynchrony as a predictor of human dynamic response to cardiac resynchronization. The authors use a cardiovascular computational model CircAdapt to characterize the isolated effect of intrinsic interventricular or intraventricular activation on resynchronization therapy response that is the change in LV dP/dt max. The simulated change in LV dP to dt max had a range of 1.3 to 26.5% increased considerably with increasing inter ventricular dyssynchrony. In contrast, the isolated effect of intra ventricular dyssynchrony was limited with the change in the LV dP/dt max range and the left ventricle from 12.3 to 18.3% in the right ventricle from 14 to 15.7%.                                                 Secondly, electrocardiographic imaging derived activation characteristics of 51 CRT candidates were used to create individual models of ventricular activation in CircAdapt. The model predicted change in LV dP/dt max was close to the actual value in left bundle branch block patients with 2.7% difference between measured and simulated when only intrinsic interventricular dyssynchrony was personalized. Among non left bundle branch block patients a change in LV dP/dt max was systematically over predicted by CircAdapt with a 9.2% difference between measured and simulated. Adding intra ventricular activation to the model did not improve the accuracy of response prediction. The authors found that computer revealed intrinsic interventricular dyssynchrony is the dominant component of the electrical substrate driving the response to CRT.                                                 In the next paper Kenji Kuroki and associates examined the use of voltage limit adjustment of substrate mapping and fast Fourier transform analysis of local ventricular bipolar electrograms during sinus rhythm to predict VT isthmuses. They performed these studies and nine post infarction patients who underwent catheter ablation for total of 13 monomorphic ventricular tachycardias. Relatively higher voltage areas on electroanatomical map or defined as high voltage channels, which were further classified as full or partial if the entire or more than 30% of the high voltage channel was detectable. 12 full high voltage channels were identified in seven of nine patients. Relatively higher fast Fourier transform areas were defined as high frequency channels, which were located on seven of 12 full high voltage channels. Five VT isthmuses or 71% were included in the seven full high voltage channels positive in high frequency channel positive sites.                                                 While no VT isthmuses were found in five full high voltage channel positive but high frequency channel negative sites, high frequency channels were identical to 9 out of 16 partial high voltage channels. Eight VT isthmuses or 89% were included in nine partial high voltage channel positive in high frequency channel positive sites, whereas no VTs isthmuses were found in the seven partial high voltage channel positive and high frequency channel negative sites.                                                 All high voltage channel positive in high-frequency channel positive sites predicted VT isthmus with a sensitivity of 100% and specificity of 80%. The authors concluded that based on this small series that combined use of voltage, limited adjustment and fast Fourier transform analysis may be useful method to detect VT isthmuses.                                                 In the next study, John Whitaker and associates examined the use of lesion index, LSI index, a proprietary algorithm combining contact force, radio-frequency application duration, and RF current. Cardiac CT was used to assess atrial tissue thickness. Ablation lines two to three per animal were created in the right atrium in seven mini pigs with point lesions using 25 watts of energy. Two weeks after the ablation, serial sections of targeted atrial tissue or examine histologically to identify gaps and transmural ablation. LSI guidelines had a lower incidence of histological gaps. Four gaps in the 69 catheter moved or 5.8% compared to ablation using LSI plus two millimeter lines in which there is seven gaps in 33 catheter moves or 21.2% and using LSI plus four millimeter lines in which there are 15 gaps in 23 moves or 65.2% p less than 0.0. The change in LSI was calculated retrospectively is a distance between two adjacent lesions above the mean LSI of the two lesions. Changing LSI values of 1.5 or less were associated with no gaps in transmural ablation.                                                 The authors concluded that in this mod of chronic atrial ablation delivery of uninterrupted transmural linear lesions may be facilitated using LSI to guide catheter movement. When change in LSI between adjacent legions is 1.5 millimeters or lower, no gaps in atrial linear lesions should be expected.                                                 In our next paper, Matthew Bennett and associate examined whether their response to antitachycardia pacing in patients with ICD could further discriminate ventricular from super ventricular arrhythmias in patients receiving ATP in the RAFT trial. The RAFT trial randomized 1,798 patients with New York Heart Association class two or three heart failure, left ventricular ejection fraction less than or equal to 30%, in QRS duration 120 millisecond or greater, to an ICD plus or a minus cardiac resynchronization. Beginning with 10,916 ATP attempts for 8,150 tachycardia episodes in 924 patients, the author's excluded tachycardias where ATP terminated the episode or were the specific etiology tachycardia was uncertain. In this study, they analyzed 3,676 ATP attempts delivered to 2,046 tachycardia episodes in 541 patients. The authors found that a shorter difference between the post pacing interval is PPI minus TCL, was more likely to be associated with VT than SVT, mean of 138.1 milliseconds for VT and 277.4 milliseconds for SVT p, less than 0.001. A PPI minus TCL value of less than or equal to 300 milliseconds had a sensitivity in 97.4% and a specificity of 28.3% for VT.                                                 The authors concluded that specifically the PPI minus TCL following antitachycardia pacing may help distinguish ventricular from supraventricular arrhythmias.                                                 In the next study, Shailee Shah and Amr Barakat and associates examined the outcomes after repeat AF ablation. The authors examined 137 patients out of a total of 10,378 patients undergoing Afib ablation who had had initial long-term success defined from recurrent arrhythmias for greater than 36 months off anti-arrhythmic drugs in subsequent underwent repeat ablation for recurrent atrial fibrillation. The median arrhythmia free period that define long-term success was 52 months. In redo-ablations reconnection of at least one of the pulmonary veins was found in 111 or 81% of patients. Additional non PV ablations were performed in 127 or 92.7% of patients. After a mean follow-up of 17 months, 103 patients or 75% were arrhythmia-free, 79 off anti-arrhythmics, and 24 on arrhythmics. The authors found that repeat ablations with re-isolation to the point of veins and modifying the atrial substrate had a good success rate.                                                 In the next article Qiongling Wang and associates hypothesized that genetic inhibition of CaMKII oxidation in a mouse model of Duchenne muscular dystrophy can alleviate abnormal calcium homeostasis thus preventing ventricular arrhythmias. The authors tested whether the selective loss of oxidation of the CaMKII effects ventricular arrhythmias in the mouse model of Duchenne muscular dystrophy. Genetic inhibition of ox-CaM kinase II by knocking replacement of the regulatory domain methionines with valines, which we'll call MMVV, prevented ventricular tachycardia in the mdx mice. Confocal calcium imaging of ventricular myocytes, isolated from the mdx MMVV mice revealed normalization of intra-calcium release events compared to myocytes from the mdx mice. Abnormal action potentials as assessed by optical mapping mdx were also alleviated by genetic inhibition of ox-CaMK II. Knockout of the NADPH oxidase regulatory sub-unit P 47 Fox normalized elevated ox-CaMK II, repaired intracellular calcium hemostasis and rescued inducible ventricular arrhythmias in the mdx mice. The authors concluded that inhibition of ROS or ox-CaMK II protects against pro-arrhythmic intracellular calcium handling, preventing ventricular arrhythmias in a mouse model of Duchenne muscular dystrophy.                                                 In the next article, Kyohei Marume and Teruo Noguchi and associates examined whether the combination of QRS duration of 120 milliseconds or greater in late gadolinium enhancement is a precise prognostic indicator for the primary endpoint of all cause death and a composite of sudden cardiac death or aborted sudden cardiac death in 531 patients with dilated cardiomyopathy. They also analyzed the association between the combination of late gadolinium enhancement and increased QRS duration in these end points among patients with a class one indication for implantable defibrillator. The author's divided study patients in three groups according to late gadolinium enhancement in QRS duration. Two negative indices that is late gadolinium enhancement negative and narrow QRS, one positive index with either late gadolinium enhancement positive or wide QRS or two positive indices late gadolinium positive and wide QRS and followed them for 3.8 years. Multiple variable Cox regression analysis identified to positive indices as significant predictors of all cause death. A hazard ratio of 4.29 p equals 0.026. Among the 317 patients with a class one indication for ICD, the five year event rate of sudden cardiac death or aborted sudden cardiac death was lowest in the two negative indices groups, 1.4%. With propensity score matching cohorts the two negative indices group had a significant lower event rate of sudden cardiac death or aborted sudden cardiac death than to two other groups hazard ratio 0.2, p equals 0.046.                                                 The authors concluded that the combination of late gadolinium enhancement in wide QRS provides additional prognostic stratification compared to late gadolinium enhancement status alone.                                                 In the next study, Matthew Sulkin and associates examined whether a novel local impedance measurement on an ablation catheter identifies catheter tissue coupling and is predictive of lesion formation. The author's first studied explanted hearts, 10 swine, and then in vivo 10 swine, using an investigational electro anatomical mapping system that measures impedance from an ablation catheter with mini electrodes incorporated into the distal electrode. Rhythmia and Intellanav, Boston Scientific.                                                 Explanted tissue was placed in a warmed 37 degree celsius saline bath mounted on a scale, and the local impedance was measured 15 millimeters away from the tissue to five millimeters of catheter tissue compression at multiple catheter angles. Lesions were created for 31 and 50 watts from 5 to 45 seconds for an N of 70. During in vivo valuation of the local impedance measurements of the myocardium 90 and blood pool 30 were guided by intracardiac ultrasound while operators were blinded to the local impedance data. Lesions were created with 31 and 50 watts for 45 seconds in the ventricle with an n of 72. The local impedance of myocardium, which was 119.7 ohms, was significantly greater than in blood pool 67.6 ohms the p of less than 0.01. Models that incorporate local impedance drop to predict lesion size had better performance that models incorporate force time integral r squared of 0.75 versus r squared of 0.54 and generator impedance drop r squared of 0.2 versus r squared of 0.58. Steam pops displayed a significantly higher starting local impedance and a larger change in local impedance compared to successful RF applications, p less than 0.01.                                                 The authors concluded that local impedance recorded for miniature electrodes provides a valuable measure of catheter tissue coupling and the change in local impedance is predictive of lesion formation during RF ablation.                                                 In the next paper, Boaz Avitall and associates found that the rising impedance recorded from a ring electrode placed two millimeters from the cryoballoon signifies ice formation covering the balloon surface and indicates ice expansion. The authors studied 12 canines in a total of 57 pulmonary veins, which were targeted for isolation. Two cryoapplications were delivered per vein with a minimum of 90 and a maximum 180 second duration. Cryoapplications was terminated upon reaching a 500 ohm change from baseline. Animals recovered 38 plus or minus six days post procedure, and the veins were assessed electrically for isolation. Heart tissue was histological examined. Extra cardiac structures were examined for damage. Pulmonary vein isolation was achieved in 100% of veins if the impedance reached 500 ohms in 90 to 180 seconds. When the final impedance was between 200 and 500 ohms within 180 seconds of freeze time, pulmonary vein isolation was achieved in 86.8%. For impedance of less than 200 ohms pulmonary vein isolation was achieved in 14%. No extra cardiac damage was recorded. The authors found that impedance rise of 500 ohms at less than 90 seconds with a freeze time of 90 seconds resulted in 100% pulmonary vein isolation.                                                 In our final papers Sally-Ann Clur and associates examined left ventricular isovolumetric relaxation time as the potential diagnostic marker for fetal Long QT Syndrome. Left ventricular isovolumetric contraction time, ejection time, left ventricular isovolumetric relaxation time, cycle length, and fetal heart rate were measured using pulse doppler wave forms in fetuses. Time intervals were expressed as percentage of cycle length, and the left ventricular myocardium performance index was calculated. Single measurements were stratified and compared between Long QT Syndrome fetuses and controls. Receiver operator curves were reformed for fetal heart rate in normalized left ventricular isovolumetric relaxation time. A linear mixed effect model including multiple measurements was used to analyze fetal heart rate, the left ventricular iso volume metric relaxation time, and the left ventricular myocardial performance index. There were 33 Long QT fetuses in 469 controls. In Long QT fetuses the left ventricular isovolumetric relaxation time was prolonged in all groups, p less than 0.001, as was the left ventricular isovolumetric relaxation time.                                                 The best cutoff to diagnose Long QT syndrome was the normalized left ventricular isovolumetric relaxation time greater than equal to 11.3 at less than or equal to 20 weeks, giving a sensitivity in 92% and a specificity of 70%. Simultaneous analysis of the normalized left ventricular isovolumetric relaxation time and fetal heart rate improved the sensitivity and specificity of Long QT Syndrome, AUC of 0.96. The normalized left ventricular isovolumetric relaxation time, the left ventricular myocardial performance index, and fetal heart rate trends differed significantly between Long QT Syndrome fetuses and controls throughout gestation.                                                 The authors concluded that left ventricular volumetric relaxation time is Prolonged QT fetuses. Findings of a prolonged normalize left ventricular isovolumetric relaxation time, and sinus bradycardia can improve the prenatal detection of fetal Long QT Syndrome.                                                 That's it for this month, but keep listening. Suraj Kapa will be surveying all journals for the latest topics of interest in our field. Remember to download the podcasts On the Beat. Take it away Suraj. Suraj Kapa:                          Thank you, Paul and welcome back to On the Beat were we will be summarizing hard-hitting articles across the entire electrophysiologic literature. Today we'll be starting within the realm of atrial fibrillation where we're review an article within the realm of anticoagulation and stroke prevention. Quon et al. published in last month's issue of JACC cardiac electrophysiology on anticoagulant use and risk of ischemic stroke and bleeding in patients with secondary atrial fibrillation. It is well known that use of anticoagulation in atrial fibrillation can reduce overall thromboembolic outcomes. However, its role in secondary atrial fibrillation is unclear. Thus, the authors sought to evaluate the effects anticoagulant use on stroke and bleeding risk. Amongst those where atrial fibrillation occurred in the setting of acute coronary syndrome, pulmonary disease, or sepsis. Amongst around 2300 patients evaluated retrospectively there was no evidence of a lower incidence of ischemic stroke among those treated with anticoagulants compared to those who are not.                                                 However, anticoagulation was associated with a higher risk of bleeding in those with new onset AF associated with acute pulmonary disease. The authors suggest as a result that there is unclear overall benefit for long-term anticoagulation in patients with presumed secondary atrial fibrillation. The difficulty in assessing this is how to define secondary atrial fibrillation. However, in many studies patients who developed in the setting of acute illness still had a high risk of developing quote unquote clinically significant AF in long-term follow-up. However, this was not necessarily absolute as many patients not necessarily develop AF that could be considered clinically significant. Thus, the clinical question that arises is: how long should we treat a patient with anticoagulation when they have presumed secondary atrial fibrillation. These data seem to suggest that there may be no net overall benefits. In other words, all-comers with secondary atrial fibrillation should not necessarily be forever treated with anti-coagulation. However, this slightly requires clinical trials to evaluate further.                                                 Next we delve into the realm of cardiac mapping and ablation where we view an article by Gaita et al. entitled 'Very long-term outcome following transcatheter ablation of atrial fibrillation. Are results maintained after 10 years of follow-up?', published in Europace last month. While pulmonary vein isolation is a widely accepted approach for treatment of atrial fibrillation, most reported studies review outcomes in terms of freedom of AF over a relatively short time period, generally two to five years. However longer term follow up is inconsistently reported. Gaita et al. sought to review 10 year outcomes amongst 255 patients undergoing ablation in a single center. They noted 52% remainder arrhythmia-free amongst a mixed cohort of both paroxysmal and persistent patients while 10% progressed to permanent atrial fiBrillation. They found that absence of increases in blood pressure, BMI, and fasting glucose was protective against an arrhythmia recurrence.                                                 These findings suggest that in a relatively small cohort of patients limited to a single center that even long-term outcomes after pulmonary vein isolation are generally quite good, exceeding 50%. However, future freedom from atrial fibrillation is heavily tied to control of other risk factors. In other words, if a patient is going to have poor control of diabetes, blood pressure, or gain weight, the benefit of their pulmonary vein isolation over long-term follow-up is likely less. These data thus highlight both the potential long-term benefit of PVI, but also the importance of counseling patients regarding the need for continued management and control of future and existing risk factors.                                                 Staying within the realm of atrial fibrillation we next review an article by Weng et al. entitled 'Genetic Predisposition, Clinical Risk Factor Burden, and Lifetime Risk of Atrial Fibrillation' published in last month's issue of circulation. The probability of detecting atrial fibrillation in patients based on clinical factors and genetic risk is unknown. Weng et al. sought to clarify whether a combination of clinical and polygenic risk scores could be used to predict risk of developing atrial fibrillation over long-term followup in the Framingham Heart Study. Amongst 4,600 individuals, 580 developed incident atrial fibrillation and had an overall lifetime risk of developing atrial fibrillation of 37%. Those are the lowest risk tertile based on clinical risk factor burden and genetic predisposition had a lifetime risk of 22% versus 48% in the highest. Furthermore, a lower clinical risk factor burden was associated with delayed atrial fibrillation onset. In order to identify patients with atrial fibrillation, before negative sequelae such as stroke occur, patient and physician understanding of risk and monitoring needs is necessary. The fact is that it will be great to identify every single patient who has atrial fibrillation before they have a negative sequela of that atrial fibrillation such as ischemic stroke.                                                 However, performing continuous monitoring of all patients with potential negative sequelae of atrial fibrillation is extraordinarily difficult. The reason is it's excessively costly. We cannot monitor the entire population irrespective of whatever the risk factors are. However, if we're able to identify the highest risk cohorts early on before the atrial fibrillation onsets, this may offer opportunities for use of newer cheaper monitors. The work by Weng et al. suggests one such possible approach combines clinical and polygenic risk scores. Actionability of these data, however, remains to be seen and further validation other cohorts is necessary to clarify generalized ability.                                                 The next article we review is published in last month's issue of the Journal of American College of Cardiology by Lopes at al. entitled 'Digoxin and Mortality in Patients With Atrial Fibrillation. Lopes et al. sought to evaluate the impact of the Digoxin on mortality in patients with atrial fibrillation and the association with the Digoxin serum concentration and heart failure status. They value this association in over 17,000 patients. At baseline 32% were receiving Digoxin. Baseline Digoxin use did not associate with risk of death, but even in these patients a serum concentration of greater than 1.2 nanograms per milliliter was associated with a 56% increase in mortality risk. For each .5 nanogram per milliliter increase in oxygen concentration the hazard ratio increased by 19% for overall mortality. This was irrespective of heart failure status. Furthermore, in patients who are newly started in Digoxin over the follow-up period, the risk and death and sudden death was higher. These data suggests a significant risk associated with Digoxin use for management of atrial fibrillation irrespective of heart failure status. Furthermore, serum valleys above 1.2 require close consideration of dose de-escalation. Whether there is any optimal dose, however, from the study is unclear. These data amongst a host of prior data strongly suggest again strategic use of Digoxin  principally for the management of atrial fibrillation.                                                 Moving on within the realm of atrial fibrillation, we review an article published in last month's issue of Circulation Research by Yan et al. entitled Stress Signaling JNK2 Crosstalk with CaMKII Underlies Enhanced Atrial Arrhythmogenesis. In this more acellular based study the mechanism underlying atrial arrhythmogenesis associated with aging was evaluated. Yan et al. sought to figure out whether the stress response JNK in calcium mediated arrhythmias might contribute to atrial arrhythmogenesis in aged transgenic mouse models. They demonstrated significant increased activity of JNK2 and aging atria, those furthermore associated with rhythmic remodeling. This association was mediated through CaMKII and ryanodine receptor channel function, with activation of the former leading to increased calcium leak mediated by the ladder. This in turn related to increase atrial fibrillation likelihood. Identifying novel targets for atrial fibrillation therapy is critical. Given atrial fibrillation is a complex disease process related to a multitude of risk factors it can be assumed that the contribution of any single factor may be mediated through distinct mechanisms.                                                 Aging in particular as well regarded, but considered to be non-modifiable risk factor for atrial fibrillation. Identifying genes or pathways, the immediate aging associated fibrillation, may take the risk of aging as no longer a non-modifiable thing. The finding of the significance of JNK2 and associate downstream effects with AF risks and aging hearts may hold potential in offering unique therapeutic targets.                                                 Finally, within the realm of atrial fibrillation, we're viewing article by Chen et al. in last month's issue of the Journal of the American Heart Association entitled Association of Atrial Fibrillation With Cognitive Decline and Dementia Over 20 Years: The ARIC-NCS Study. Multiple studies have suggested a significant association between atrial fibrillation risk of dementia. However, these studies have limited time follow-up and were often done and predominantly white patients. Thus, the authors sought to use the data from ARIC, the Atherosclerosis Risk in Communities Neurocognitive Study, to assess the risk of cognitive decline associated with atrial fibrillation. Amongst over 12,000 participants, a quarter of whom are black and half of whom are white, they noted 2100 patients developed atrial fibrillation and 1,150 develop dementia over a 20 year follow up period.                                                 There was a significantly greater risk of cognitive decline amongst those who developed atrial fibrillation. In turn incident atrial fibrillation for the follow-up period was associated with a higher risk of dementia even after adjusting for other clinical and cardiovascular risk factors such as incidents that ischemic stroke. These data further strengthened prior evidence of a direct link between atrial fibrillation and risk of cognitive decline and dementia. Understanding this long-term risk raises the need to additionally identify approaches to prevent this occurrence, which in turn is dependent on understanding the underlying mechanisms. The finding that the risk of cognitive decline dementias independent of ischemic stroke events raises concern that either subclinical micro-embolic events or other factors may be playing a role in this risk and in turn raises question as to how best to prevent them. Until better understood, however, the question of whether the association is causal remains to be seen.                                                 Changing gears yet again, we now delve into the realm of ICDs, pacemakers and CRT. Published in last month, issue of Heart Rhythm Tarakji et al. published a paper entitled 'Unrecognized venous injuries after cardiac implantable electronic device transvenous lead extraction.' Overall risk of transvenous lead extraction includes that of potentially fatal venous laceration. The authors sought to evaluate the incidence of venous injury that may be unrecognized based on microscopic study of extracted leads. Amongst 861 leads obtained from 461 patients they noted 80 leads or almost 9%. Amongst 15% of patients showed segments vein on the lead body, most of which were transmural including the tissue layer. However, in terms of clinical significance, only 1% had need for emergent surgical intervention for clinically significant venous laceration. Risk factors for having the entire vein on the lead included age of lead, ICD leads, and the use of the laser sheath.                                                 These findings suggest that there may be a high incidence of subclinical venous injury after lead extraction though rarely resulting clinically apparent sequelae. As would be expected, venous injury, including transmural removal of portions of the vein traversed by the lead, was more common amongst older leads, which generally more often require laser sheets and ICD leads. The question is however, whether this carries any direct clinical implications. One they may be considered is the potential additive risk of an advancing new lead through the same venous channel, particularly in the setting of potential transmural venous injury that already exists.                                                 Next in last month's issue of Heart Rhythm we review an article by Sharma at al. entitled 'Permanent His-bundle pacing as an alternative to biventricular pacing for cardiac resynchronization therapy: A multicenter experience.' The use of resynchronization therapy for treatment of patients with heart failure and wide QRS has been shown to offer morbidity and mortality benefits. However, many patients maybe non-responders, and recent studies on His bundle pacing of suggested potential clinical benefits. His bundle pacing essentially only requires one pacing catheter attached within the region of the His bundle Sharma et al. sought to evaluate the safety and success rates of His bundle pacing for patients who have either failed standard resynchronization therapy or in whom most tried as a primary intervention. They noted His bundle pacing was successful in 90% of patients with reasonable myocardial and His bundle capture thresholds. Patients in both groups exhibits significant narrowing of QRS morphology and improvement in left ventricular ejection fraction from a mean of 30 to 43%. However, a total of seven patients had lead related complications.                                                 These database on a retrospective analysis of two types of patients, those failing standard biventricular therapy, and those on whom his bundle pacing was attempted as a primary modality suggest overall safety and efficacy in a handful of experienced centers. The promise of His bundle pacing is that a may allow for more effective resynchronization than standard approaches. The high rate of success suggests that His bundle pacing maybe both safe and reasonable to pursue. However randomized trials across more centers are needed to fully prove its benefit, particularly as a primary modality of treatments.                                                 Next we review ICDs and chronic kidney disease. In last month's issue of JAMA cardiology by Bansal at al. entitled 'Long-term Outcomes Associated With Implantable Cardioverter Defibrillator in Adults With Chronic Kidney Disease.' While the benefit of ICDs in patients with low EF is widely recognized, modifying factors that may increase risk of death are not as well defined. These include things like advanced age and chronic kidney disease. Bansal et al. sought to evaluate long-term outcomes and ICD therapy in patients with chronic kidney disease. In retrospective study of almost 5,900 ambulatory patients amongst whom 1550 had an ICD, they found no difference in all cause mortality. However, ICD placement was associated with an increased risk of subsequent hospitalization due to heart failure or any cause hospitalization.                                                 In light of recent studies such as DANISH the robust sense of ICD benefit is being questioned. One of the thoughts for the absence of similar benefit to prior studies lies in the improving care of ambulatory heart failure patients. In patients with chronic kidney disease several questions rises to the risk with ICD, including infectious risk in dialysis patients and the concomitant mortality risk with renal dysfunction. The author suggested in retrospective study, no incremental benefit of ICDs in patients with chronic kidney disease and perhaps some element of added risk is related to hospitalization. However, this study has several limitations. It is retrospective and many patients received ICDs may have been perceived to be sicker in some way. Thus care must be taken in interpretation, but consideration of randomized studies to adjudicate benefit are likely necessary.                                                 Finally, within the realm of devices, we reviewed an article by Tayal et al. entitled "Cardiac Resynchronization Therapy in Patients With Heart Failure and Narrow QRS Complexes.' publishing the Journal of American College of Cardiology last month. Several parameters have been stressed to identify benefit of resynchronization therapy in patients with wide QRS include cross correlation analysis with tissue doppler imaging. However, many patients may have evidence in mechanical dyssynchrony even in the absence of an apparent wide QRS thus Tayal et al. sought to evaluate the benefit of resynchronization therapy amongst 807 patients with heart failure and a narrow QRS mean criteria in a randomized study. Of the 807 46% had delayed mechanical activation. Those without delay mechanical activation had underwent we standardization therapy and were associated with worse overall outcomes likely due to new delayed mechanical activation potentially related to CRT pacing. These data support the absence of a role for resynchronization therapy in patients with a narrow QRS. This is expected as resynchronization therapy likely offers the most benefit in patients with mechanical dyssynchrony that results from electrical dyssynchrony.                                                 Since by its very nature resynchronization therapy relies on non physiologic cardiac pacing thus compared to normal cardiac activation the nature of resynchronization pacing is desynchronization. These data support the absence of a role for resynchronization therapy in patients with heart failure and narrow QRS complexes.                                                 Moving on to cellular electrophysiology we review an article by Kozasa et al. published in last month's issue of Journal of Physiology entitled 'HCN4 pacemaker channels attenuate the parasympathetic response and stabilize the spontaneous firing of the sinoatrial node.' Heart rate is controlled by an interplay between sympathetic and parasympathetic components. In turn HCN4 abnormalities have been implicated in congenital sick sinus syndrome. The authors sought to clarify the contribution of HCN4 to sinus node autonomic regulation. They created a novel gain-of-function mouse where the HCN4 activity could be modulating from zero to three times normal. They then evaluated ambulatory heart-rate variability and responsive heart rate to vagus nerve stimulation. They found HCN4 over-expression did not increase heart rate, but attenuated heart-rate variability. It also attenuated bradycardic response to vagus nerve stimulation. Knockdown of HCN4 in turn lead to sinus arrhythmia and enhanced parasympathetic response. These data suggest HCN4 attenuates sinus node response to vagal stimuli thus stabilizing spontaneous firing of the node. The clinical application of this remain to be seen but are maybe important in that they highlight a mechanism for a heretofore poorly understood mechanism for how exactly HCN4 abnormalities may lead to sick sinus syndrome.                                                 Within the realm of ventricular arrhythmias we highlighted a number of articles published this past month. The first article we review was published in last month's issue of JACC clinical electrophysiology, entitled characterization of the electrode atomic substrate and cardiac sarcoidosis: correlation with imaging findings of scarring inflammation published by [inaudible 00:41:40] et al. In patients with cardiac sarcoidosis one of the questions is how to define the electronic atomic substrate, particularly before we entered the electrophysiology laboratory. Both active inflammation and replacement fibrosis maybe be seen in patients. The authors evaluated in 42 patients with cardiac sarcoidosis, the association between an abnormal electrograms and cardiac imaging findings including PET and Computed Tomography, as well as Cardiac MRI. They noted that amongst these 40 patients, a total of 21,000 electrograms were obtained, and a total of 19% of these were classified as abnormal. Most of the abnormalities occurred in the basal paravalvular segments and intraventricular septum. They further noted that many of these abnormalities in terms of electrograms were located outside the low voltage areas, particularly as it relates to fractionation. In about 90% of patients they notice late gadolinium enhancements and they noted abnormal FDG uptakes suggesting active inflammation in about 48%.                                                 However, it should be noted that only 29 of the 42 patients underwent cardiac imaging. Segments with abnormal electrograms tended to have more late gadolinium enhancement evidence scar transmurality, and also they noted that the association of abnormal PET scan did not necessarily occur with abnormal electrograms. Thus, they concluded that in patients with cardiac sarcoidosis and ventricular tachycardia pre-procedural imaging with cardiac MRI could be useful in detecting electroanatomic map abnormalities that may in turn be potential targets for substrate ablation. However, they were more likely associated with more scar transmurality and lower degrees of inflammation on PET scanning. These data are important in that they highlight potential non-invasive means by which to understand where substrate might occur in patients with the cardiac sarcoidosis. It is well recognized that cardiac sarcoidosis is associated with increased risk of ventricular arrhythmias. These risks have increased ventricular arrhythmias, might be targetable with ablation. Newer therapies might even offer non invasive means by which to perform ablation in patients best. Thus if we could identify non based on mechanisms of identifying the substrate, this will be even more critical.                                                 The critical findings of this particular paper lie in noting that most of the abnormalities still is in intra ventricular sePtum in basal segments, and also that it is MRI in late gadolinium enhancement and associates more with the abnormal electrograms. Interestingly, the absence of inflammation correlating with the presence of more abnormal electrograms suggests that it is not so much the act of inflammation as being reflected in the endocardial map, but the existence of scar.                                                 Next, again within JACC clinical electrophysiology we review an article by Porta-Sánchez et al. entitled 'Multicenter Study of Ischemic Ventricular Tachycardia Ablation With Decrement Evoked Potential Mapping With Extra Stimulus.' The authors sought to conduct a multicenter study of decrement evoked potential base functional tech ventricular tachycardia substrate modification to see if such mechanistic and physiologic strategies could result in reduction in VT burden. It is noted that really only a fraction of the myocardium in what we presume to be substrate based on the presence of low voltage areas are actually involved in the initiation and perpetuation of VT. Thus if we can identify the critical areas within the presumed substrate for ablation, this would be even a better way of potentially honing in on our targets. They included 20 consecutive patients with ischemic cardiomyopathy. During substrate mapping fractionated late potentials were targeted and an extra stimulus was provided to determine which display decrements. All patients underwent DEEP focus ablation with elimination being correlated with VT non-inducibility after radio-frequency ablation. Patients were predominantly male, and they noted that the specificity of these decrement evoked potentials to detect the cardiac isthmus for VT was better than that of using late potentials alone. They noted 15 of 20 patients were free of any VT after ablation of these targets over six months of follow-up, and there was a strong reduction in VT burden compared to six months pre ablation.                                                 They concluded that detriment evoked potential based strategies towards ablation for ventricular tachycardia might identify the functional substrate and those areas most critical to ablation. They in turn regarded that by its physiologic nature it offers greater access to folks to ablation therapies.                                                 This publication is important in that it highlights another means by which we can better hone in on the most critical regions for substrate evaluation in patients with ventricular tachycardia. The fact is more extensive ablation is not necessarily better and might result in increased risk of harm if we think about the potential effects of longer ablations or more ablation lesions. Thus if we could identify ways of only targeting those areas that are most critical to the VT circuits, we could perhaps short and ablation procedural time, allow for novel ways of approaching targeted ablation with limited amounts of ablation performed, or perhaps even improve overall VT outcomes by knowing the areas that are most critical to ensure adequate ablation therapy provided. However, we need to understand that this is still a limited number of patients evaluated in a non randomized manner. Thus whether or not more extensive ablation performed might have been better is as of yet unclear                                                 Staying within the realm of ventricular tachycardia we review an article published in last month's issue of Heart Rhythm by Winterfield et al. entitled the 'Impact of ventricular tachycardia ablation on healthcare utilization.' Catheter ablation of atrial tachycardia has been well accepted to reduce recurrent shocks in patients with ICDs. However, this is a potentially costly procedure, and thus effect on overall long-term health care utilization remains to be seen. The authors sought to evaluate in a large scale real world retrospective study the effect of VT ablation on overall medical expenditures in healthcare utilization. A total 523 patients met study inclusion criteria from the market scan database. After VT ablation median annual cardiac rhythm related medical expenditures actually decreased by over $5,000. Moreover the percentage of patients with at least one cardiac rhythm related hospitalization an ER visit decreased from 53 and 41% before ablation respectively, to 28 and 26% after ablation. Similar changes we're seeing in number of all cause hospitalizations and ER visits. During the year before VT ablation interestingly there was an increasing rate of healthcare resource utilization, but a drastic slowing after ablation.                                                 These data suggests that catheter ablation may lead to reduced hospitalization in overall healthcare utilization. The importance of these findings lies in understanding why we do the things we do. We can provide a number of therapies to patients, but we seek two different effects. One is the individual effect of improving their particular health. The second thing is trying to avoid increasing healthcare expenditures on a population level and making sure resources are utilized. If we can reduce recurrent hospitalizations and overall healthcare expenditure in patients by providing a therapy in addition to provide individual benefit, this is the optimal situation. These data suggests that VT ablation might provide such a benefits, that in fact it reduces overall healthcare utilization while improving overall outcomes.                                                 Next and finally within the realm of ventricular arrhythmias, we review more on the basic side the role of Titin cardiomyopathy leads to altered mitochondrial energetics, increased fibrosis and long-term life-threatening arrhythmias, published by Verdonschot et al. in last month's issue of European Heart Journal. It is known now that truncating Titin variants might be the most prevalent genetic cause of dilated cardiomyopathy. Thus, the authors sought to study clinical parameters and long term outcomes related to Titin abnormalities in dilated cardiomyopathy. They reviewed 303 consecutive and extensively phenotype dilated cardiomyopathy patients who underwent cardiac imaging, Holter monitoring, and endomyocardial biopsy and in turn also underwent DNA sequencing of 47 cardiomyopathy associated genes. 13% of these patients had Titin abnormalities. Over long-term followup they noted that these patients had increased ventricular arrhythmias compared to other types of dilated cardiomyopathy, but interestingly, they had similar survival rates. Arrhythmias in those Titin abnormal patients were most prominent in those who were subjected to an additional environmental trigger, including viral infection, cardiac inflammation, other systemic disease or toxic exposure. They also noted the cardiac mass was relatively reduced in titan admirable patients.                                                 They felt that all components of the mitochondrial electron transport chain we're simply up-regulated in Titin abnormal patients during RNA sequencing and interstitial fibrosis was also augmented. As a result, they concluded that Titin variant associated dilated cardiomyopathy was associated with an increased risk of ventricular arrhythmias, and also with more interstitial fibrosis. For a long time we have reviewed all non ischemic cardiomyopathy as essentially equal. However, more recent data has suggested that we can actually hone in on the cause. In turn, if we hone in on the cause, we might be able to understand the effects of specific therapies for ventricular arrhythmias based on that underlying cause. Patchy fibrosis might not be as amenable, for example, to ablation as discreet substrate that we might see in infarct related VT. Understanding the relative benefit in very specific types of myopathies might hold benefit in understanding how to, one, risk stratify these patients, and two, understand what type of therapy, whether pharmacologic or ablative, might result in greatest benefit to the patients.                                                 Changing gears entirely now to the role of genetics, we review multiple articles in various genetic syndromes published this past month. First, we reviewed an article by Providência et al. published in the last month's issue of heart entitled 'Impact of QTc formulae in the prevalence of short corrected QT interval and impact on probability and diagnosis of short QT syndrome.' The authors sought to assess the overall prevalence of short corrected QT intervals and the impact on diagnosis of short QT syndrome using different methods for correcting the QT interval. In this observational study they reviewed the sudden cardiac death screening of risk factors cohorts. They then applied multiple different correction formulae to the ECGs. They noted that the prevalence of individuals with the QTc less than 330 and 320 was extremely low, namely less than .07 and .02% respectively. They were also more frequently identified using the Framingham correction. The different QTc correction formulae could lead to a shift of anywhere from 5 to 10% of individuals in the cohort overall.                                                 They further noted, that based on consensus criteria, instead of 12 individuals diagnosed with short gut syndrome using the Bazett equation, a different number of individuals would have met diagnostic criteria with other formulae, 11 using Fridericia, 9 with Hodges, and 16 using the Framingham equation. Thus, they noted that overall the prevalence of short QT syndrome exceedingly low and an apparently healthy adult population. However, reclassification as meeting criteria might be heavily dependent on which QT correction formula is used. The importance of these findings is that not all QTs are created equal.                                                 Depending on how you compute the QT interval in which formula to use may affect how you actually risk characterize a patient. Unfortunately, these data do not necessarily tell us which is the right formula, but this highlights that it might be relevant to in the future evaluate the role of different formulae and identifying which is the most necessary to classify a patient.                                                 Moving on to an article published in last month's issue of the journal of clinical investigation by Chai et al. we review an article entitled 'Physiological genomics identifies genetic modifiers of Long QT Syndrome type 2 severity.' Congenital Long QT Syndrome is a very well recognized, inherited channelopathy associated life-threatening arrhythmias. LQTS type 2 is specifically caused by mutations in casein to encoding the potassium channel hERG. However, even with the mutation not all patients exhibit the same phenotype. Namely some patients are more at risk of life threatening arrhythmias in spite of having the same mutation as others who do not exhibit the same severity phenotype. The authors sought to evaluate whether specific modifiable factors within the remaining genetic code might be modifying the existing mutation. Thus, they sought to identify contributors to variable expressivity in an LQT 2 family by using induced pluripotent stem cell derived cardiomyocytes and whole exome sequencing in a synergistic manner.                                                 They found that patients with severely effected LQT 2 displayed prolonged action potentials compare to sales from mildly effected first-degree relatives. Furthermore, stem cells derived from patients were different in terms of how much L-type calcium current they exhibited. They noted that whole exome sequencing identified variants of KCNK17 and the GTP-binding protein REM2 in those patients with more severe phenotypes in whom greater L-type calcium current was seen. This suggests that abnormalities or even polymorphisms in other genes might be modifying the risk attributed to by mutations in the primary gene. This showcases the power of combining complimentary physiological and genomic analysis to identify genetic modifiers and potential therapeutic targets of a monogenic disorder. This is extraordinarily critical as we understand on one level that when we sequence a monogenic disorder that there might exist variants of uncertain significance, namely they have not been classified as disease causing, but could be. In turn, we also recognize that mutations in a family might effect different relatives differently. However, why this is has been relatively unclear.                                                 If we can understand and identify those patients who are most at risk of dangerous abnormal rhythms, this will be useful in how much to follow them, and what type of therapy to use in them. The fact that other genes might modify the risk even in the absence of specific mutations, suggests that novel approaches to characterizing the risk might help for the risk modified patients classification in general. Clinical use, however, remains to be seen.                                                 Moving on from long QT, we evaluate 'The Diagnostic Yield of Brugada Syndrome After Sudden Death With Normal Autopsy' noted in last month's issue of the Journal of American College of Cardiology and published by Papadakis et al. It is well known, the negative autopsies are not uncommon in patients, however, families might be wondering how at risk they are. Thus, the authors sought to assess the impact of systematic ajmaline provocation testing using high right precordial leads on the diagnostic yield Brugada syndrome in a large cohort of Sudden Arrhythmic Death syndrome families. Amongst 303 families affected by Sudden Arrhythmic Death Syndrome evaluation was done to determine whether or not there was a genetic inherited channelopathy cause. An inherited cardiac disease was diagnosed in 42% of the families and 22% of relatives Brugada syndrome was the most prevalent diagnosis overall amongst 28% of families. Ajmaline testing was required, however, to unmask the Brugada Syndrome in 97% of diagnosed individuals. Furthermore, they use of high right precordial leads showed a 16% incremental diagnostic yield of ajmaline testing for diagnosing Brugada syndrome.                                                 They further noted that a spontaneous type 1 regard or pattern or a clinically significant rhythmic event developed in 17% of these concealed regardless syndrome patients. The authors concluded the systematic use of ajmaline testing with high right precordial leads increases the yield of Brugada Syndrome testing in Sudden Arrhythmic Death Syndrome families. Furthermore, they noted that assessments should be performed in expert centers or patients could also be counseled appropriately. These findings are important and one of the big questions always becomes how aggressively to test family members of patients or of deceased individuals who experienced sudden arrhythmic death. Many of these patients have negative autopsies, and genetic autopsy might not be possible due to lack of tissue or blood products that can be adequately tested.                                                 The data here suggest that amongst a group of 303 sudden arrhythmic death, families that Brugada Syndrome is by far the most frequent diagnosis. If an inherited cardiac disease was identified. In turn, it is not ECG alone or echo alone that helps identify them, but requires drug provocation testing in addition to different electrode placements. Whether or not this will consistently offer benefit in patients in general or my result in overcalling remains to be seen next within the realm of genetic predisposition.                                                 We view an area where we don't know if there's a genetic predisposition in article published by Tester et al. entitled Cardiac Genetic Predisposition in Sudden Infant Death Syndrome in last month's issue of the journal of american college of cardiology. Sudden Infant Death Syndrome is the leading cause of post-neonatal mortality and genetic heart diseases might underlie some cases of SIDS. Thus the authors sought to determine the spectrum and prevalence of genetic heart disease associated mutations as a potential monogenic basis for Sudden Infant Death Syndrome. They study the largest cohort to date of unrelated SIDS cases, including a total of 419 individuals who underwent whole exome sequencing and targeted analysis for 90 genetic heart disease susceptibility genes. Overall, 12.6% of these cases had at least one potentially informative genetic heart disease associated variants. The yield was higher in those mixed European ancestry than those of European ancestry.                                                 Infants older than four months were more likely to host a potentially informative gene. Furthermore, they noted that only 18 of the 419 SIDS cases hold a [inaudible 01:01:26] or likely pathogenic variant. So in other words, only 4% of cases really had a variant that they could say was distinctly pathogenic or likely pathogenic. Thus, overall, the minority of SIDS cases have potentially informative variant in genetic heart disease susceptibility gene, and these individuals were mostly in the 4 to 12 month age group. Also, only 4% of cases had immediately clinically actionable variance, namely a variant, which is well recognized as pathogenic and where we could actually say that a specific therapy might have had some effect. These findings can have major implications for how best to investigate SIDS cases in families. It might suggest that SIDS cases where the individual was older, nearly 4 to 12 months of age might have a greater yield in terms of identifying variance.                                                 While this might not affect the deceased in fit, it might affect, families are planning on having another child in whom a variant can be identified.                                                 Finally, within the realm of genetics, we review an article published in last month's issue of Science Advances by Huang. et al. entitled 'Mechanisms of KCNQ1 Channel Dysfunction in Long QT Syndrome Involving Voltage Sensor Domain Mutations'. Mutations that induce loss of function of human KCNQ1 underlie the Long QT Syndrome type 1. While hundreds of mutations have been identified the molecular mechanism by which they result in impaired function are not as well understood. The authors sought to investigate impact of 51 specific variants located within the voltage sensor domain and emphasized effect on cell surface expression, protein folding, and structure. For each variant efficiency of trafficking of the plasma membrane, impact of proteasome inhibition, and protein stability were evaluated. They noted that more than half of the loss of function mutations were seen to destabilized structure of the voltage sensor domain, generally accompanied by mistrafficking and degradation by the proteasome.                                                 They also noted that five of the folding defective Long QT Syndrome mutant sites were located in the S0 helix, where they tend to interact with a number of other loss of function mutation sites in other segments of the voltage sensor domain. They suggested these observations reveal a critical role for the S0 helix as a central scaffold to help organize and stabilized KCNQ1 overall. They also note the importance of these findings is that mutation-induced destabilization of membrane proteins may be a more common cause of disease functioning in humans. The importance of these findings lies in better understanding why specific mutations lead to appa

Commentary by Dr. Valentin Fuster

Pako y Titin estan de regreso para hablar de el delicado tema de Rafael Marquez, un poco de el comienzo de la liga mx, los sorprendentes lobos buap, las definiciones de penal de el America contra Pumas y el comienzo de una temporada mas de Fantasy Football.

Over the last 12 months, Nordics have become a key criterion and point of progression for most of our athletes. In today's episode, we go deep on why we love them,  - why they are better than a deadlift and RDL for brute eccentric hamstring strength  - the mistake we made regarding Corelfits  - why the Nordic isn't quite perfect - why sport doesn't serve the hamstring well  - how eccentrics affect the collagen and titan in your muscles  - and how you can start adding them in without being sore for a week Some resources: This video from David Opar should provide a great summary of all things hamstrings: https://www.youtube.com/watch?v=48MAhno35Lg David Opar and the hamstring injury research group have done a heap of work on the Nordic and its effect on injury risk (this link will take you to a heap of their academic papers which you can read for free) https://scholar.google.com.au/scholar?q=david+opar+hamstring&hl=en&as_sdt=0&as_vis=1&oi=scholart&sa=X&ved=0ahUKEwjXoPXP6rjSAhXDEpQKHefTBAkQgQMIFzAA Also the Nordbord website: https://valdperformance.com/ Fascicle length: http://www.jsams.org/article/S1440-2440(12)00580-4/abstract More on Titin (not Titan): http://jeb.biologists.org/content/217/16/2825.long And collagen content of muscles: http://jap.physiology.org/content/97/1/197.long (a small study but Jacob seems to be onto something)

Pourquoi ce titre, « Allégorie japonaise » ? J'aime à voir dans ce pays une « exacerbation ». Dans la recherche de raffinement mais aussi dans les excès de l'hyper modernité. Et l'ampleur de la catastrophe de Fukushima nous rappelle que notre « aventure » humaine n'aura qu'un temps. Différentes phases se succèdent dans cette oeuvre : La nature, l'apparition de l'homme : sons évoquant des musiques traditionnelles, l'accélération du temps et la modernité : les trains, l'américanisation de la société : les guitares électriques. Enfin l'énergie nucléaire, symbolisée par une vibration électrique et cet effet de « déchirement du son », généré par d'innombrables micro-coupures qui représentent la radio-activité, son effet insidieusement et intimement destructeur. Site du projet Meanwile in Fukushima : http://fukushima-open-sounds.net

Pourquoi ce titre, « Allégorie japonaise » ? J'aime à voir dans ce pays une « exacerbation ». Dans la recherche de raffinement mais aussi dans les excès de l'hyper modernité. Et l'ampleur de la catastrophe de Fukushima nous rappelle que notre « aventure » humaine n'aura qu'un temps. Différentes phases se succèdent dans cette oeuvre : La nature, l'apparition de l'homme : sons évoquant des musiques traditionnelles, l'accélération du temps et la modernité : les trains, l'américanisation de la société : les guitares électriques. Enfin l'énergie nucléaire, symbolisée par une vibration électrique et cet effet de « déchirement du son », généré par d'innombrables micro-coupures qui représentent la radio-activité, son effet insidieusement et intimement destructeur. Site du projet Meanwile in Fukushima : http://fukushima-open-sounds.net

  Carolyn: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center and Duke-National University of Singapore. Today's featured discussion deals with the perspective piece entitled, What I Wish Clinicians Knew About Industry and Vice Versa. Intriguing, isn't it? I can tell you it is one of the best papers I have ever read, so stay tuned. First, here's your summary of this week's journal.     The first study takes a step towards understanding atrial fibrillation on a more fundamental level by demonstrating that some patients have altered left ventricular myocardial energetics even in the absence of other comorbid diseases. First author, Dr. [Veejay Surendra 00:00:50], corresponding author, Dr. [Cassidy 00:00:53] and colleagues from the University of Oxford studied 53 patients with lone atrial fibrillation undergoing catheter ablation and compared them to 25 matched controls without atrial fibrillation. They did this using sequential studies of cardiac function with magnetic resonance imaging as well as energetics with phosphorus-31 magnetic resonance spectroscopy.     At baseline, there was subtle but significant left ventricular dysfunction and abnormalities in ventricular energetics in patients relative to controls. Following ablation of atrial fibrillation, left ventricular function measured by ejection fraction and peak systolic circumferential strain improved rapidly with a switch to sinus rhythm but remained at normal at 6 to 9 months. Although pulmonary vein isolation effectively eliminated atrial fibrillation in all the patients in the study, the hearts continued to express an energetic profile consistent with a myopathic phenotype meaning that the ratio of phosphocreatine to adenosine triphosphate was lower in the atrial fibrillation compared to controls irrespective of recovery of sinus rhythm and freedom from recurring atrial fibrillation.     The clinical implications of these findings are that apparently lone atrial fibrillation may actually be a consequence rather than a cause of an occult cardiomyopathy and that this cardiomyopathy is unaffected by ablation. Of course, future studies are needed to prove this and to examine whether therapeutic strategies that target the adverse cardiometabolic phenotype could reduce atrial fibrillation recurrence. These important issues are discussed in an accompanying editorial by Doctors Hyman and Callans.     The next study provides experimental evidence that suggests we may finally have an answer to heart failure preserved ejection fraction or HFpEF, and that is the modification of titin. Titin is a sarcomeric protein that functions as a molecular spring and contributes greatly to left ventricular passive stiffness. The spring properties can be tuned through post-transcriptional and post-translational processes and their derangement has been shown to contribute to diastolic dysfunction in patients with HFpEF. The current paper by first author, Dr. Methawasin, corresponding author, Dr. Granzier and colleagues from University of Arizona provide important proof of principal investigation of the effects of manipulation of titin isoforms as a treatment for a transverse aortic constriction murine model of progressive left ventricular hypertrophy leading to HFpEF.     Conditional expression of a transgene with deletion of the RNA recognition motif for one of the splicing factor, RBM20 alleles, resulted in reduced splicing and a substantial increase in larger more compliant titins that were named super compliant titin. The result was normalization of passive stiffness of isolated muscle strips as well as normalization of left ventricular diastolic function and chamber stiffness as assessed by echocardiography and pressure volume analyses. There were no effects on extracellular matrix stiffness. The authors also showed that other spliced targets of RBM20 did not contribute to the results and thus, the beneficial effects were almost certainly entirely related to the changes in titin isoforms.     Furthermore, treadmill exercise was used to show that treated animals displayed improved exercise tolerance. In summary, the study showed that increasing titin compliance in this murine model resulted in marked improvement in multiple measures of diastolic function and performance, thus suggesting that titin holds promise as a therapeutic target in HFpEF. This is the discussed in an excellent accompanying editorial by Dr. LeWinter and Dr. Zile.     The next study adds importantly to evidence that heavy physical exertion and anger or emotional upset may act as triggers of first myocardial infarction. In this paper by first author, Dr. Smith, corresponding author, Dr. Yusuf, and colleagues from the Population Health Research Institute Hamilton Health Sciences and Master University, authors explored the triggering association of acute physical activity, anger, and emotional upset with acute myocardial infarction. They did this in the inter-heart study which was a case control study of first acute myocardial infarction in 52 countries. In the current analysis, the authors used a case crossover approach to estimate odds ratios for acute myocardial infarction occurring within 1 hour of triggers.     Of 12,461 cases, 13.6% engaged in physical activity and 14.4% were angry or emotionally upset in the case period referring to the 1 hour before symptom onset. Physical activity in the case period was associated with an increased odds of acute myocardial infarction with an odds ratio of 2.3 and a population attributable risk of 7.7%. Anger or emotional upset in the case period was associated with an increased odds of acute myocardial infarction of more than 2.4 odds ratio and a population attributable risk of 8.5%. Importantly, there was no effect modification by geographic region, prior cardiovascular disease, cardiovascular risk factor burden, prevention medications, time of day, or day of onset of acute myocardial infarction.     Interestingly, the authors did find an interaction between heavy physical exertion and anger or emotional upset with an additive association in participants with exposure to both in the 1 hour prior to the acute myocardial infarction. The take home message, these findings suggest that clinicians should advice patients to minimize exposure to extremes of anger or emotional upset due to the potential risk of triggering an acute myocardial infarction. While heavy or vigorous physical exertion may also be a trigger, this did not refer to just any physical activity and the authors cautioned that this must be balanced against the known well-established benefits of regular physical activity over the long term and clinicians should continue to advice patients about the life-long benefits of exercise.     The last study provides insights in the molecular mechanism in pulmonary hypertension. First author, Dr. Lee, corresponding author, Dr. Stenmark, and colleagues from the Pediatric Critical Care Meds and CVP Research University of Colorado Denver hypothesized that metabolic reprogramming to aerobic glycolysis may be a critical adaptation of fibroblast in the hypertensive vessel wall, an adaptation that drives proliferative and pro-inflammatory activation through a mechanism specifically involving increased activity of the NADH sensitive transcriptional corepressor, C-terminal-binding protein 1.     The authors assessed glycolytic reprogramming and measured NADH to NAD+ ratio in bovine and human adventitial fibroblast as well as mouse lung tissues. They found that expression of the C-terminal-binding protein 1 was increased in fibroblast within the primary adventitia of humans with idiopathic pulmonary arterial hypertension and animals with pulmonary hypertension. Furthermore, treatment of fibroblast from the pulmonary hypertensive vessels of hypoxic mice with a pharmacological inhibitor of C-terminal-binding protein 1 led to a normalization of proliferation inflammation and the aberrant metabolic signaling.     In summary, these result showed that C-terminal-binding protein 1, a transcription factor that is activated by increased free NADH acts as a molecular linker to drive the proliferative and pro-inflammatory phenotype of adventitial fibroblast within the hypertensive vessel wall. Thus, this metabolic sensor may be a more specific target for treating metabolic abnormalities in pulmonary hypertension. Those were your summaries. Now for our feature paper. Our feature today is special on so many levels, and because it's so special, I actually have Dr. Joe Hill, editor-in-chief of circulation from UT Southwestern here today with me. Hi Joe.   Joe: Sure. As always, it's a pleasure to be here with you. This is a new type of content where we solicit thought leaders from a variety of vantage points around the cardiovascular space to provide their perspective on the future of cardiovascular Science in medicine. Rob Califf, the FDA Commissioner, provided his perspective on the regulatory role interfacing with cardiovascular medicine and Science. Victor Dzau who presides over the National Academy of Medicine in the United States did the same, provided a very insightful perspective from his vantage point now, formerly in academia, but now overseeing this advisory board to the policy makers in Congress. Today, we're going to talk about a perspective that emerges from industry, from someone who also has a strong and long history in academia.   Carolyn: That is a perfect lead up. The title of the paper; What I Wish Clinicians Knew About Industry and Vice Versa. Here is the amazing guest that we have today, it's Dr. Ken Stein, Chief Medical Office of Rhythm Management at Boston Scientific. Hi Ken. It is a very, very intriguing title and I'd like you to first describe to us what makes you the person who can talk about being a clinician and going over to the dark side of industry and vice versa?   Ken: Thanks Carolyn and Joe. I think right now just get over my embarrassment at being called a thought leader and being mentioned in the same as Rob Califf and Victor Dzau. I met both of them but I don't think I've ever been mentioned in the same sentence as either them and probably never will be again. Why me to do this? Again very gracious of Joe to invite the submission. My history, I've been in industry now at Boston Scientific for 7 years, and prior to that was an unreformed academic faculty at Cornell. Ever since I did my training, eventually becoming co-director of the EP Lab there for many years. Then 7 years ago, the opportunity came up to leave the cloistered ivory towers of academia and to join industry. It's been a very interesting and I think very productive ride ever since.   Carolyn: I have to tell you that your article is just one of the most well-written pieces I have ever read and I mean that sincerely. You began with the story that everybody asked you this question. Why did you do it? What did you learn? I'm going to ask that of you today. Tell us.   Ken: In the 7 years, I get 2 questions all the time. One is, do you miss practice? The answer is, there are things about practice that I miss very deeply and that is really the engagement that you get with patients and families. I think we always have to remember as caregivers, we're privileged to be able to do what we do. On the other hand is, but I do get an opportunity to participate in decisions now that rather than affect one patient at a time, for better or for worse, affect hundreds of thousands of patients at a time.     The other question is, what surprised you? What have you learned? What didn't you know about industry? As I thought about it, it's 2 things. It's one that I think in retrospect I was and I think many of us are way too cynical about the motivations of industry, how industry operates. The other shock, if you will, was that it goes 2 ways and there's a lot of cynicism in industry about physician motivations and how physicians operate on a day to day basis.   Carolyn: Really? Do you have any examples of that?   Ken: I'll give you a couple of examples. First, from the point of view of how does industry work and what are the motivations in industry. One of the first decisions that I had to make 7 years ago after joining the company was to issue a recall on one of our products. It actually was a recall that had not yet failed in the field but we had some bench testing that suggested that there was a particular risk to some patients and novel to the industry and the whole thing. This is not go over well with the CEO, but in fact, really the only question people ask is, is this the right decision for patients? That was a really gratifying piece of education to me.     The flip side of the coin, we did introduce a new battery technology in our fibrillators and CRT devices just before I joined the company that basically doubled the amount of battery capacity that we have in the devices. It's one of the funny things. There are still editorials being written in journals other than circulation, I'll say, that still say that industry will never increase battery longevity of their devices but cost us money because we lose money on device replacements. We've done it and a lot of our competitors are in the process of doing it.     When I got to the company, what I found is there was a tremendous amount of angst within the leadership of the company. Do doctors do this or are they afraid in a fee-for-service environment to give up what they get doing battery replacements on short-lived devices. Of course that cynicism is unfounded. That doctors have embraced longer, better battery life technology.   Joe: Ken, to hear you say this is interesting and frankly inspiring. You can't pick up a copy of the New York Times right now and not read about some issue around drug pricing and some of the companies that have done the wrong thing with. They've increased prices hundreds of percentage, 400%, even more. To know from your perspective that those are perhaps the exceptional circumstances and that there are many, many companies who of course have to keep a business running but at the same time they truly have the patient at heart. You have said and you said in your piece that as the Chief Medical Officer, you're the voice of the patient at your organization.   Ken: I aim to be. That was the lesson I learned from Don Baim who really ... Don passed away very shortly after I joined the company, who's really a giant in cardiology. I wish that I had been able to spend more time with him as a mentor but that was very important statement he made. Say he's right, there are bad actors, there are bad actors in industry, there are bad actors among physicians, there are bad actors among academics, but that's not generally true. I also want to be careful not to be misconstrued. Skepticism and doubt are important. Cogito ergo sum, it's not just I think, therefore I am, it's probably better understood that I doubt, therefore I think, therefore I am. Skepticism is fundamental to scientific process, but there's this border that you cross over where constructive skepticism turns into destructive cynicism. I'm afraid gets in the way of our ability to work together to better the outcomes, better welfare of patients.   Carolyn: Do you think we've swung from the United States maybe you could give me your opinion to the wrong end of that balance between constructive skepticism and destructive cynicism? Joe, what do you think?   Joe: As someone who has not worked in my own research closely with industry, sometimes I think that we have. I mean, there are certainly many examples. We all know where people have crossed the line and that is profoundly unacceptable, but at the same time, I worry that we've thrown the baby out with the bathwater and some of the things that are uniquely done in academia and some of the things that are uniquely done in industry, a synergy between them across the divide is essential to move this field forward. I think sometimes the boundaries and the bright lines separating them are so distinct and defined that it prevents those source of synergies.   Carolyn: Thank you for that paper that really provides that balanced perspective. The beautiful thing, it's just so personal almost. It feels like we're sitting with you, having a conversation when we're reading that paper. Like now, it's just been an amazing experience having you on this podcast. Do you have any last messages?   Ken: My last words. I again just want to thank you and thank Joe. Has the pendulum swung too far? Thing about pendulums are that they oscillate and I think what's needed is a willingness to watch out that it doesn't swing too far. Is there cynicism? I'll admit, I was flabbergasted and I still flabbergasted that you allowed me to write this piece but I think the fact that you welcomed the piece from someone in industry within the intent of bringing this out, that is the pendulum not going too far. As long as there are voices, editors, journals who are willing to help us articulate points like this, I think that's at least what keeps us in a reasonable balance.   Joe: As Carolyn said, you brought a uniquely human conversational element to this piece. Not everybody would publish a piece in circulation and acknowledge that you are intimated and embarrassed walking into Don Baim's office. That brought us right into your living room and that was powerful.   Ken: Honestly, I wasn't looking for the job. I was more interviewing them to find out what I can about the company, but I did not want to make an ass of myself in front of them. I felt like I was [pieing 00:19:53] for fellowship. I walked in the door and honestly I'm still standing with my hand on the doorknob and he looks up at me and I have to remember his voice, he had that deep sort of growly voice. He said, "Stein, you have no idea what Chief Medical Officer does, do you?" I'm just thinking, do I try to BS my way out of this or do I just give him the God honest truth and turn around and go back to work. I said, "No, Dr. Baim." I couldn't call him [inaudible 00:20:22] and to the end, I told him, "Dr. Baim," I said, "I had no idea." That's when he said, "Your job is to be the voice of the patient within Boston Scientific." He said after that, "You don't need to know anything about business. We know you don't know anything about business. We've got a lot of MBAs and hopefully they do."   Carolyn: Thank you once again for the paper, for this discussion. Thank you both for being here. For all of you who are listening, thank you for joining us again on Circulation on the Run.    

Programme de Michel TITIN-SCHNAIDER pour webSYNradio : 10 ans de constructions sonores. Retour sur les dix premières années de constructions sonores de Michel Titin-Schnaider. Ingénieur de métier et musicien autodidacte il cherche avant tout à rester libre de tout style ou dogme pré-établi et à créer "son" univers sonore en toute liberté (utiliser un instrument autrement, naviguer entre différents styles musicaux selon une idée directrice…un thème). Il utilise souvent des instruments virtuels (orchestre symphonique) mais dans des compositions qui ne sont pas pensées pour être jouables. En écoute des extraits de ses albums et une attention de plus en plus marquée pour l'univers de la danse butô.

Genetically modified, or GM, crops are a hot topic. Some people are deeply suspicious of the technology while others see it as an effective and efficient way of generating bountiful, healthier harvests. Plus, purple tomatoes, a giant of a gene involved in heart disease, and what's in a name? We take a look at the naming of genes. Like this podcast? Please help us by supporting the Naked Scientists

Patrick Whaley is the founder & CEO of Titin Tech, the world's only weighted compression gear. Titin is doing extremely well, having revenues of $1,000,000+ in May of 2014 alone. Titin was also featured on Shark Tank and received an investment from Daymond John to help take his business to the next level.  In this episode you will learn: The lessons Patrick learned starting his first business in kindergarten. How to have a strong work ethic when the odds are against you.  How Patrick took Titin tech from $10,000 in monthly revenue to $1,000,000/MO in only 7 months. How being shot and almost killed changed Patrick's life. How Patrick brought his company back from near bankruptcy.  How to make an income & an impact in this world.    For full show notes: www.teenpodcast.com/31

Today's guest Patrick Whaley is a former Georgia Tech grad, gun shot survivor and super hard working entrepreneurial juggernaut. His company and mission center around uncompromising quality and better training gear to revolutionize athletics. The Titin Compression Campaign Success Quote "You only live once." -YOLO Links Titin Tech Epic Books Barbarians at the Gate: The Fall of RJR Nabisco   Connect with Patrick @TitinTech Titin's Facebook Love the Show? Leave us a Review    

It's a massive molecular record breaker. Andrew Holding introduces Titin, the largest protein in the human body

« Japon (le 6 mai le Japon s'est réveillé sans énergie nucléaire) » est une pièce de musique anecdotique de 25 min. Une sorte de voyage fantasmé mêlant sans cesse modernité, nature et tradition. Cette pièce est dansée par Lorna Lawrie (danse butoh). Elle a été jouée lors de la dernière semaine culturelle du Japon à Mérida (Vénézuela). Projet Meanwhile in Fukushima : http://fukushima-open-sounds.net

« Japon (le 6 mai le Japon s'est réveillé sans énergie nucléaire) » est une pièce de musique anecdotique de 25 min. Une sorte de voyage fantasmé mêlant sans cesse modernité, nature et tradition. Cette pièce est dansée par Lorna Lawrie (danse butoh). Elle a été jouée lors de la dernière semaine culturelle du Japon à Mérida (Vénézuela). Projet Meanwhile in Fukushima : http://fukushima-open-sounds.net

Programme Michel Titin-Schnaider pour webSYNradio : QUELQUES AVENTURES ELECTRO-ACOUSTIQUES. Retour sur les dix premières années de constructions sonores de Michel Titin-Schnaider. Ingénieur de métier et musicien autodidacte il cherche avant tout à rester libre de tout style ou dogme pré-établi et à créer "son" univers sonore en toute liberté (utiliser un instrument autrement, naviguer entre différents styles musicaux selon une idée directrice…un thème). Il utilise souvent des instruments virtuels (orchestre symphonique) mais dans des compositions qui ne sont pas pensées pour être jouables. En écoute des extraits de ses albums et une attention de plus en plus marquée pour l'univers de la danse butô.