Podcasts about smad3

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.22.550041v1?rss=1 Authors: Paul, D., Srivastava, A., Banerjee, J., Tripathi, M., Doddamani, R., Lalwani, S., Siraj, F., Sharma, M. C., Chandra, P. S., Dixit, A. Abstract: Inflammation and blood brain barrier (BBB) damage are associated with epileptogenesis in Mesial Temporal lobe epilepsy with Hippocampal sclerosis (MTLE-HS). Animal studies have predicted the role of Matrix metalloproteinase 9 (MMP9) in extracellular matrix (ECM) modulation, BBB leakage and neuro-inflammation, while Transforming growth factor beta (TGF{beta}) signalling in astrocytes potentiates hyper-excitability leading to seizure generation. We hypothesize whether changes in activity and expression of MMP9, and the ratio of MMP9 and its inhibitor, Tissue inhibitor of metalloproteinase 1 (TIMP1), have a role in epileptogenesis in the patients with MTLE-HS through zona occludens 1 (ZO1) modulation. We also proposed the role of astrocytic TGF{beta} signalling in these patients. mRNA expression of MMP9 and TIMP1 was significantly up-regulated. The ratio of MMP9 to its inhibitor TIMP1 was greater than one, suggesting activation of MMP9, further confirmed by gelatin zymography. MMP9 activity as well as immunoreactivity was higher in patients with MTLE-HS as compared to non-seizure controls, whereas the immunoreactivity of ZO1 was significantly lower in the patients. The downstream TGF{beta} signalling effector molecules, SMAD3 and pSMAD3 immunoreactivity were also significantly higher in MTLE-HS patients and both molecules showed co-localisation with astrocytes in the hippocampal region. Further, we showed preliminary data about interaction of MMP9 and TGF{beta}1 in these patients as evidenced by a co-immunoprecipitation assay. This study highlighted the MMP9 and astrocytic TGF{beta} signalling mediated potential mechanism of epileptogenesis in MTLE-HS patients. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Dr. Ralph W. Moss and son Ben discuss the healing and preventive properties of the readily available, inexpensive and delicious, humble little parsley plant.   Join us for another fascinating journey as we dive 'Beyond the Garnish' into the remarkable world of parsley and its component, Apigenin. This humble herb, often relegated to the sidelines of our plates, holds an impressive secret - the potential to significantly impact the fight against cancer. Program Notes: For more information on cancer-fighting foods and supplements, please visit our website: https://www.themossreport.com 5 Defenders Mushroom Blend https://shop.realmushrooms.com/products/organic-mushroom-blend-capsules?ref=391 “A comprehensive self-help plan for cancer includes medicinal mushrooms. They are indispensable”. – Ralph W. Moss, PhD Olive Oil From the Raw https://www.olivefromtheraw.com/?aff=2 “A study of over 1,000,000 people shows that daily consumption of 2 Tbsp of high quality, extra virgin olive oil that contain polyphenols, results in a 30-40% decrease in cancer incidents.” – Ralph W. Moss, PhD For Dr. Moss' recommended products list, please visit https://www.themossreport.com/recommended-products/ The full scope of research on apigenin and cancer: https://pubmed.ncbi.nlm.nih.gov/?term=apigenin+cancer The Indian review article: Apigenin in cancer prevention and therapy: A systematic review and meta-analysis of animal models https://pubmed.ncbi.nlm.nih.gov/35752426/ The German clinical trial: Prospective cohort comparison of flavonoid treatment in patients with resected colorectal cancer to prevent recurrence  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2703843/ Recommended parsley intake: Approximately 0.79 tablespoons or 2.37 teaspoons of chopped fresh parsley would provide 10 mg of apigenin. TAKE about one tablespoon OR THE EQUIVALENT AMT. OF DRIED PARSLEY (SEE BELOW) TWICE PER DAY. For 0.69 grams of dried parsley flakes: 0.69 grams / 0.8 grams per teaspoon ≈ 0.86 teaspoons So, approximately one teaspoon 0.86 teaspoons of dried parsley flakes would provide 10 mg of apigenin. OR TAKE THIS TWICE PER DAY. NOTE: PATIENTS IN THE GERMAN STUDY ALSO RECEIVED EGCG (GREEN TEA) AT THE SAME TIME. Based on the average amount of EGCG in one gram of Japanese Sencha green tea leaves (47.3 milligrams), and assuming that you're using one teaspoon (about 2.5 grams) of tea leaves to brew 6 ounces of tea, you can expect to get around 118.25 milligrams of EGCG in your cup of tea. A short bibliography on apigenin and cancer: Shukla S, Gupta S. Apigenin: a promising molecule for cancer prevention. Pharm Res. 2010;27(6):962-978. Salehi B, Venditti A, Sharifi-Rad M, et al. The therapeutic potential of apigenin. Int J Mol Sci. 2019;20(6):1305. Chen AY, Chen YC. A review of the dietary flavonoid, apigenin, on cancer prevention and treatment. Curr Med Chem. 2013;20(19):2570-2581. Fang J, Xia C, Cao Z, Zheng JZ, Reed E, Jiang BH. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. FASEB J. 2005;19(3):342-353. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. Kim BR, Seo HS, Ku JM, et al. Apigenin inhibits cancer stem cell-like phenotypes in human glioblastoma cells via suppression of c-Met signaling. Phytother Res. 2016;30(5): 800-807. Lu L, Sun T, Chen X, et al. Apigenin inhibits epithelial-mesenchymal transition of human colon cancer cells through the AKT/GSK-3β/Snail signaling pathway. Oncol Rep. 2016;35(1):369-374. Lu Z, Xu S, ER P, et al. Apigenin inhibits the self-renewal capacity of human ovarian cancer SKOV3-derived sphere-forming cells. Mol Med Rep. 2015;11(4): 2850-2856. Wang J, Wu J, Zhang X, et al. Apigenin suppresses the growth of colorectal cancer cells by targeting Twist-mediated epithelial-mesenchymal transition. Mol Med Rep. 2018;17(5): 7305-7310. Yao J, Zhao L, Zhao Q, et al. Apigenin inhibits ovarian cancer stem cell-like properties through the modulation of the Twist1/TGF-β1/Smad3 pathway. Oncol Rep. 2016;36(1): 512-520. For Dr. Moss' Red, Green, and Green Tea Smoothie recipes, visit The Moss Report. These smoothie recipes are just some examples of how you can incorporate natural compounds with potential health benefits into your diet.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.07.330407v1?rss=1 Authors: Gori, I., George, R., Purkiss, A., Strohbuecker, S., Randall, R. A., Ogrodowicz, R., Carmignac, V., Faivre, L., Joshi, D., Kjaer, S., Hill, C. S. Abstract: Shprintzen-Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys-Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-{beta} signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional corepressor SKI, which is a negative regulator of TGF-b signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing and biochemistry to show that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3. This results in stabilization of SKI and consequently attenuation of TGF-{beta} responses, in both knockin cells expressing an SGS mutation, and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-b-induced transcriptional responses, and not enhancement, which has important implications for other Marfan-related syndromes Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.12.247874v1?rss=1 Authors: Bacon, K., Blain, A., Bowen, J., Burroughs, M., McArthur, N., Menegatti, S., Rao, B. M. Abstract: Quantifying the binding affinity of protein-protein interactions is important for elucidating connections within biochemical signaling pathways, as well as characterization of binding proteins isolated from combinatorial libraries. We describe a quantitative yeast-yeast two hybrid (qYY2H) system that not only enables discovery of specific protein-protein interactions, but also efficient, quantitative estimation of their binding affinities (KD). In qYY2H, the bait and prey proteins are expressed as yeast cell surface fusions using yeast surface display. We developed a semi-empirical framework for estimating the KD of monovalent bait-prey interactions, using measurements of the apparent KD of yeast-yeast binding, which is mediated by multivalent interactions between yeast displayed bait and prey. Using qYY2H, we identified interaction partners of SMAD3 and the tandem WW domains of YAP from a cDNA library and characterized their binding affinities. Finally, we showed that qYY2H could also quantitatively evaluate binding interactions mediated by post-translational modifications on the bait protein. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.28.224469v1?rss=1 Authors: Jeon, K.-I., Huxlin, K. R. Abstract: Following injury to the peripheral and central nervous systems, tissue levels of transforming growth factor (TGF)- {beta} 1 often increase, which is key for wound healing and scarring. However, active wound regions and scars appear to inhibit process outgrowth by regenerating neurons. We recently showed that corneal wound myofibroblasts block corneal nerve regeneration in vivo, and sensory neurite outgrowth in vitro in a manner that relies critically on TGF-{beta}1. In turn, delayed, abnormal re-innervation contributes to long-term sensory dysfunctions of the ocular surface. Here, we exposed morphologically and biochemically-differentiated sensory neurons from the ND7/23 cell line to TGF-{beta}1 to identify the intracellular signals regulating these anti-neuritogenic effects, contrasting them with those of Semaphorin(Sema)3A, a known inhibitor of neurite outgrowth. Neuronal morphology was quantified using phase-contrast imaging. Western blotting and specific inhibitors were then used to identify key molecular mediators. Differentiated ND7/23 cells expressed neuron-specific markers, including those involved in neurite extension and polarization. TGF-{beta}1 increased phosphorylation of collapsin response mediator protein-2 (CRMP2), a molecule that is key for neurite extension. We now show that both glycogen synthase kinase (GSK)-3 {beta} and Smad3 modulate phosphorylation of CRMP2 after treatment with TGF-{beta}1. GSK-3 {beta} appeared to exert a particularly strong effect, which could be explained by its ability to phosphorylate not only CRMP2, but also Smad3. In conclusion, TGF-{beta}1s inhibition of neurite outgrowth in sensory neurons appears to be regulated through a highly-conserved signaling pathway, which involves the GSK-3 {beta} /CRMP-2 loop via both canonical and non-canonical mechanisms. It is hoped that by defining the signaling pathways that control neurite outgrowth in wound environments, it will become possible to identify optimal molecular targets to promote re-innervation following injury. Copy rights belong to original authors. Visit the link for more info

Treg and Th cells are under transcriptional modulation via cytokine mediated control of a Nfil3 protein that serves to block FOXp3 expression.DR Guerra verifies the evidence in the data from a recent paper: Experimental & Molecular Medicine volume 51, Article number: 80 (2019) that demonstrated Inhibition of the TGF-β signaling pathway led to increased Nfil3 expression which blocked Foxp3 transcription via SMAD3. This is an important contribution to the T lymphocyte literature as it points to the proximal and distal modulation of T cell lineage differentiation, thus focusing attention to potential pharmacotherapeutic and immunoepigenetic mechanisms to control inflammation in diseases such as IBD while simultaneously suggesting strategies to reorganize the T cell profile to destroy tumors. Dr Daniel J Guerra, Authentic Biochemistry. 17 August 2019. --- Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

Cindy S.H.:                         Hi. Welcome to Discover CircRes, the monthly podcast of the American Heart Association's journal Circulation Research. I'm your host, Cindy St. Hilaire, and my goal is to bring you highlights of articles published in the Circ Research Journal as well as have in-depth conversations with senior scientists and the junior trainees who have led the most exciting discoveries in our current issues. Today is our premier episode, so I want to take some time to introduce myself, give you a little bit of background about the history of the journal, and then have a conversation with our new editor in chief, Dr. Jane Freedman, and my social media editor partner in crime, Dr. Milka Koupenova. Cindy S.H.:                         First, a little bit about me. I'm an assistant professor of medicine and bioengineering at the University of Pittsburgh. My lab is part of the division of cardiology and we're also a member of the Pittsburgh Heart, Lung and Blood Vascular Medicine Institute. I'm still a relatively new PI. I'm still learning as I go. One of the strengths of being a new PI in the current time is the amazing network we have through social media, whether it's through listening to podcasts or through Twitter or through select groups like one of my favorites, New PI Slack. Really one of my personal goals of starting this podcast for Circ Research is to have a career development angle. Because career development is so fresh in my mind and it's really something I want to incorporate into this podcast, we're hoping we can reach out to more junior trainees through these mediums. Really that's the impetus for Dr. Freedman wanting to have specific social media editors at the Circulation Research Journal. Cindy S.H.:                         I'm very honored to be the first host of this podcast and I'm very excited for this opportunity. As a team, Milka and I hope to expose the larger community to not only the most current and exciting discoveries in cardiovascular research but also a behind-the-scenes look of what it takes to get high-impact research done and published and planned and funded, and also talk about some of the maybe the non-bench aspects of this job, the networking, the behind-the-scenes look that really you learn on the fly as you go. Hopefully we can expose more people to these on-the-fly things in a slightly more rigorous manner. Cindy S.H.:                         Before I go into the articles summarized in this week's podcast, I want to give a very big thank you to Ruth Williams. Ruth is the person who writes the content of the In This Issue which is featured in every issue of the journal Circulation Research, and that content is extremely helpful in deciding which articles we're going to focus on in this podcast and also for helping me form the conversations and discussions. Thank you, Ruth, for all your hard work. Cindy S.H.:                         Now I'm going to highlight three articles that were featured in the June 21st issue of Circulation Research. The first is entitled Relationship Between Serum Alpha-Tocopherol and Overall and Cause-Specific Mortality: A 30-Year Prospective Cohort Analysis. The first author is Jiaqi Huang and the corresponding author is Demetrius Albanes , who are both at the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, which is at the NIH in Bethesda, Maryland. Alpha-tocopherol is the more formal name for vitamin E, and vitamin E is an essential fat-soluble vitamin. By essential, that means that while your body absolutely needs it, it does not produce it itself. Therefore we need to consume products containing vitamin E. We do that by eating vegetable oils, nuts, seeds, whole grains and certain fruits and vegetables. Previously, population-based studies have shown inconsistent associations between circulating vitamin E and risk of overall death or death due to specific diseases such as cancer and cardiovascular disease. Cindy S.H.:                         To look more closely at cause-specific mortality, Huang and colleagues studied a cohort of close to 30,000 Finnish men, which is a huge study. Added to that, these men were in their 50s and 60s at the start of the study and then continued for the next 30 years of their life to be in this study. It's frankly an amazing achievement to keep that many individuals enrolled. From approximately 24,000 deaths, so about 80% of the original cohort, the authors adjusted for factors such as age and confounding things like smoking. They found that vitamin E levels were inversely associated with the risk of death from a variety of causes. What that means is that higher levels of vitamin E associated with lower risk of death. All of those causes of death that they found were cardiovascular disease, heart disease, stroke, cancer, and respiratory disease. This large prospective cohort analysis provides very strong evidence that higher vitamin E levels means greater protection. Cindy S.H.:                         It's really interesting to note though that this data did not seem to associate with a reduced risk of death by diabetes or, for that matter, injury and accidents, which I guess kind of makes sense. The authors say these results indicate that vitamin E may influence longevity, but they also highlight the need for further studies, specifically in more ethnically diverse populations and of course in women, because we all know a major limiting factor of a majority of cardiovascular studies is the fact that often there are just not enough women in these studies. But really that's a push now to include not only women but more ethnically and geographically diverse populations. Cindy S.H.:                         The second article I want to highlight is titled Mitochondria Are a subset of Extracellular Vesicles Released by Activated Monocytes and Induce Type I IFN and TNF Responses in Endothelial Cells . The first authors are Florian Puhm and Taras Afonyushkin , and the senior author is Christopher Binder. All three are in the Department of Laboratory Medicine, the Medical University of Vienna, in Vienna, Austria. This group is also part of the Research Center of Molecular Medicine of the Austrian Academy of Sciences. Cindy S.H.:                         I want to talk about this paper because I found that title extremely provocative. Extracellular vesicles or microvesicles are small particles that can be released from cells. These particles can act as cell-cell communicators. They can hold a variety of substances such as proteins and micro RNAs and minerals and all sorts of things that are derived from inside the cell. The matrix vesicle is then budded off. Matrix vesicles released from monocytes after bacterial LPS stimulation, so a stimulus that induces an inflammatory response, these matrix vesicles have been shown to contain mitochondrial proteins. Mitochondrial DNA-containing matrix vesicles have been reported in the mouse model of inflammation. From this premise, from these prior studies, Dr. Puhm and colleagues hypothesized that the mitochondrial content of matrix vesicles might actively contribute to pro-inflammatory effects. Cindy S.H.:                         What they then did was show that monocytic cells release free mitochondria and also matrix vesicles that contain mitochondria within them. These free and matrix vesicle-encapsulated mitochondria were shown to drive enothelial cells to induce inflammatory cytokines such as TNF-alpha and interferon. These circulating matrix vesicles were collected also in human volunteers that were injected with this same inflammatory substance, LPS. These circulating matrix vesicles isolated from humans also induced endothelial cell cytokine production. Very interestingly, inhibition of the mitochondrial activity drastically reduced the pro-inflammatory capacity of these matrix vesicles. Cindy S.H.:                         Together, this result suggests that the released mitochondria, whether it's free or whether it's encapsulated in a matrix vesicle, may be a key player in certain inflammatory diseases. This study shows that in addition to their central role in cellular metabolism, mitochondria, whether encapsulated or free, can actively participate in an inflammatory response in a cell other than the cell it was native in, which is just intriguing to think about. This work provides new insight to the contribution of mitochondria to the content and biological activity of extracellular vesicles. It also might suggest that perhaps targeting mitochondria and their release may represent a novel point for therapeutic intervention in inflammatory pathologies. Cindy S.H.:                         The last article I want to highlight is titled Macrophage Smad3 Protects the Infarcted Heart, Stimulating Phagocytosis and Regulating Inflammation . The first author is Bijun Chen and the senior author is Nikolaos Frangogiannis . When tissues are injured, there is localized increase in the cytokine TGF-beta. However, depending on conditions, this TGF-beta can function to stimulate macrophages to adopt either pro-inflammatory or anti-inflammatory phenotypes. To complicate matters more, the signaling pathway for both the pro- and anti-inflammatory phenotypes involves activation of the intracellular signaling protein Smad3. Inflammation, whether too much or too little, can influence the outcome of injuries, including injuries such as myocardial infarctions. An infarction, for those of you unfamiliar with the term, is a localized area of dead tissue and that results from a lack of blood supply. In this case, an infarction, a myocardial infarction, is essentially a heart attack that stops blood flow through the coronaries and causes death in the cardiac tissue and cells. Cindy S.H.:                         The authors hypothesized that in the infarcted myocardium, activation of TGF-beta and Smad signaling and macrophages may regulate repair and remodeling. They had a very specific question about a very specific cell type in the context of the whole heart. To address the role of Smad3, they utilized mice that were engineered to lack Smad3 in the myeloid lineage which produces macrophage cells. They found that these mice with myeloid cell-specific deletion of Smad3 had reduced survival compared to control mice. Additionally, the hearts from the animals with the myeloid cell-specific deletion of Smad3 exhibited increased adverse remodeling and greater impairment of function. That's a really interesting finding. The heart tissue itself was the same. All that was different were the cells of the myeloid lineage. Then to dig after what cells were mediating this effect, the investigators moved on to in vitro studies. They found that Smad3-lacking cells themselves showed reduced phagocytic activity, sustained expression of pro-inflammatory genes, and reduced production of anti-inflammatory mediators when compared with control macrophages. Cindy S.H.:                         In summary, these results suggest Smad3 is necessary for macrophages in the area of the infarction to transition to an anti-inflammatory phagocytic phenotype that protects against excess remodeling. However, we cannot go after global inhibition of Smad3 as a potential therapy post myocardial infarction, and that's because inhibition of Smad3 in cardiomyocytes is actually protective against the infarction. Inhibition in a macrophage is bad, but inhibition in a cardiomyocyte is good. Any potential Smad3-modifying therapies really needs to be designed to be cell type-specific and be able to be deployed to activate that cell type. Cindy S.H.:                         In addition to science, I love history. I thought I would take this opportunity of the first podcast to share with you a little bit of history about the Journal of Circulation Research. Circulation Research is now in its 66th year, but its origins can be traced to 1944. That was when the AHA established a council that was attempting to organize its research arm and its professional program arms. The AHA journal Circulation was already in existence, but in 1951 the executive committee decided to launch a basic research supplement, and it was called just that: Circulation Basic Research Supplement. But a few years later, Circulation Research was to be its own publication because of the interest and the excitement around the basic research supplements. The quote that I'm going to read is from that first executive committee meeting and there they wanted Circulation Research to be the authoritative new journal for investigators of basic sciences as they apply to the heart and circulation. Cindy S.H.:                         It's a fun little subgroup that they list after that. They list in anatomy, biology, biochemistry, morphology, which I just think is so neat to think about, pathology, physics, pharmacology, and others. It's interesting to think about what that would be today if we were now finding this journal. Biochemistry, genetics, molecular biology. It's fun to think about how much science has changed since they began this journal. Really the broader goal was to integrate and disseminate new knowledge. Leading that was Dr. Carl Wiggers, who was the first editor in chief of Circ Research. At the time, he was the head of physiology at Western Reserve University, and he's often referred to as the dean of physiology, as his research really provided much of the fundamental knowledge regarding the pressures in the heart and the vessels of the body and how they interact. Cindy S.H.:                         I actually went back and looked at some of the first titles in Volume One, Issue One, of Circ Research. It's really kind of neat. Some of them could be completely relevant today. I'm just going to read a few. Nucleotide Metabolism and Cardiac Activity, Fundamental Differences in the Reactivity of Blood Vessels in Skin Compared to Those in the Muscle. That was at the VRIC the other day. Haemodynamic Studies of Tricuspid Stenosis of Rheumatic Origin. Reading these for the first time I actually got chills because my two themes of my lab are both in that first Volume One, Issue One, of that journal. I study the extracellular nucleotide aCD73 and its impact on vascular homeostasis. I also study calcific aortic valve disease and are hugely curious about the role of inflammation and things like rheumatic heart disease in the progression of the disease. It's amazing how much science has changed, but yet how so much has stayed the same. Cindy S.H.:                         Dr. Wiggers wrote a few gems, a few quotes in his biography that I want to share with you. I find them inspiring and also humbling. The first is, "Research is a gamble in which the laws of chance favor the loser. The loser must remain a good sport," which I think is perfect to think about in science. I really wish I had read that after my first RO1 was triaged. The next two are more about the science writing and I think they're great not only for when we're thinking about papers but also grants. The first is, "Readers are greatly influenced in their judgment of a research project by literary style. A poor presentation can easily damage the best investigation," which is so true. No matter how good your science is, if you can't communicate it, it doesn't matter. And lastly, "A good paper, like a good glass of beer, should be neither largely foam nor flat. It should have just the right amount of head of foam to make it palatable." Cindy S.H.:                         With these nuggets of wisdom, we're now going to talk with Drs. Jane Freedman, who's now the editor in chief of Circ Research, and Dr. Milka Koupenova, who is the social media editor. Before I really introduce Jane, I want to recognize all of the former editors in chief of Circ Research, Dr. Carl Wiggers, Dr. Carl Schmidt, Dr. Eugene Landis, Dr. Julius Comroe, Dr. Robert Berne, Dr. Brian Hoffman, Dr. Francis Abboud, Dr. Harry Fozzard, Dr. Stephen Vatner, Dr. Eduardo Marbán, Dr. Roberto Bolli, and now Dr. Jane Freedman. Welcome, Jane. Thank you so much for this opportunity and congratulations on your new position. Dr. Freedman:                   Thank you very much. Cindy S.H.:                         I was wondering if you could just introduce yourself to the listeners and give us a little bit about your background. Dr. Freedman:                   Sure. I am the Budnitz Professor of Medicine at the University of Massachusetts, and I originally became interested in a scientific career while attending Yale University where I was both an architecture and geology major. Cindy S.H.:                         Interesting. Dr. Freedman:                   Yes, very interesting. Then, not exactly knowing what I wanted to do, I worked for a year as a research assistant for my later-to-be mentor Dr. Joe Loscalzo at Brigham and Women's Hospital. There one day he sent me up to the intensive care unit and said we need to get a tube of blood from someone who was in the throes of having a myocardial infarction. Really at that point I became hooked. Why was that person having a heart attack, and using their blood how could I figure out whether they would live, die, do well, not do well, or yield new things that might help us cure or diagnose people with heart attacks later on? After that. I went to Tufts Medical School. I did my residency and cardiology fellowship at Brigham and Women's Hospital and the Massachusetts General Hospital. After working at several different places, I have wound up at the University of Massachusetts where I am in the Division of Cardiology and where my laboratory currently resides. Cindy S.H.:                         Excellent. As the new editor in chief, what do you see as your vision for the journal? Dr. Freedman:                   I'm in a very fortunate position to be taking over a wonderful journal from an incredibly dedicated group of editors and associate editors and other supportive editors. Scientific pursuits and reporting and publications are really evolving at a rapid clip, so we hope to have several things happen over the next few years to survive and thrive. The first thing is we hope to define and expand Circulation Research's scientific identity. We want to extend its already outstanding portfolio of science that really demonstrates how elegant basic and translational mechanisms and pathways are part of a greater web of cardiovascular disease and stroke. This will include an increasingly diverse group of basic and translational sciences and they'll touch on both fundamental studies as well as how they translate to human disease. We also want to continue to pursue the excellence that Circulation Research already epitomizes and we want to extend its brand both to an increasingly diverse group of members, both nationally and internationally. Dr. Freedman:                   Circulation Research already has really wonderful publication metrics such as turnaround time, time to review, and we hope to maintain that so as to be a journal of choice for an increasingly growing number of investigators. We would also very much like to have greater interface with the American Heart Association. A lot of the research on our pages is funded by the American Heart Association, and the majority of science that the American Heart Association currently funds is basic cardiovascular science. We hope to have greater interface and help our users of the journal understand what the American Heart Association can do for them and for their scientific pursuits. Dr. Freedman:                   Last and very importantly, we really want to attract early and mid-career investigators to the journal. We already have some really nice programs that the previous editorship has started, such as Meet The First Author, but we would also like to be a site for education of how you can review papers, have a junior editor program and other types of programs that will help early and mid-career investigators in their future. One of the ways we're going to be doing that is to have enhanced social media programs. Cindy S.H.:                         Great. I really like that idea of having the junior editors because I think the best learning experience I had about how to write a grant did not happen until I actually served on a study section, because it was there you actually can understand all of those comments you got on your first grant that was triaged and why they were said. I think that is a key and really important aspect. Dr. Freedman:                   That's a perfect analogy because you want to remove the black box that people think is happening when they send their manuscripts in. There's so many reasons why manuscripts succeed and don't succeed, and we really do want to be as transparent as possible and we do want to educate investigators as much as possible about the process. Cindy S.H.:                         Actually, could you maybe tell us a little bit about that process? I made all my figures, I formatted my paper according to the instructions, I hit submit. Black box. What happens? What's the next step? Dr. Freedman:                   What's the next step? Cindy S.H.:                         What do you do? What does an editor in chief actually do? Dr. Freedman:                   I do have to say that none of this would happen, especially in the incredibly quick turnaround time, if we didn't have amazing support and help in our office that happens to be in Baltimore. The people there are just incredible. They make sure that papers move through. It's really 24/7. Our group has not been at it for very long, but I know Dr. Bolli's group as well as our group, people are handling manuscripts as fast as they really come in. We see the manuscript, they get quality checked. We try not to be too onerous with the first steps. Then typically they go to one of the associate or deputy editors who will handle them to send out for review. Cindy S.H.:                         Is that based on keywords or the title or how is that decided? Dr. Freedman:                   Sometimes it's based on keywords, so careful with your keywords. A lot of times, because each of the associate editors has an area of expertise that hopefully covers what your science is interested in, they will know experts in the field. We very heavily rely on our editorial board. We have an amazing editorial board at Circulation Research, and amazing contributions from the BCBS council. These individuals have over the years and currently provided just tireless and unsung, devoted help to making the journal run smoothly. It's a pretty quick turnaround time. Then the decision made based on the reviews of the article. Occasionally articles come in and they're not suitable for the journal because they're not what we perceive as what our readers would be interested in. Sometimes those articles don't go up for review. We don't want to keep them caught up, so we send them back right away. Dr. Freedman:                   When the articles come back in with the reviews, we're going to be discussing them at a weekly meeting. Other viewpoints will weigh in, and then we make a decision whether it's an accept, whether it's a revise, whether it needs a lot more science. That's called a de novo. Sometimes we think it's more suitable for one of the other 11 American Heart Journals and we might suggest that you consider sending it to that journal and we consult with that journal's editor. Cindy S.H.:                         Interesting. All that happens with about 14 days. Dr. Freedman:                   That's supposed to happen with 14 days. Cindy S.H.:                         It does pretty regularly based on the stats. That's amazing. One of the initiatives you mentioned was really the role of social media. Now I would like to introduce Dr Milka Koupenova, who is the co social media editor alongside me. Before I let Milka talk, I really have to be honest and say that my graduate school days were some of the best of my life. It was in part because Milka I were both in the same lab. We overlapped by a couple of years under the amazing mentorship of Dr. Katya Ravid. Every time we get together, all we'd talk about was how can we be like Katya? Maybe someday we'll actually have a podcast where we can get Katya in here and actually record all her nuggets of wisdom. Dr. Koupenova:                 I think the same thing about Katya. Cindy S.H.:                         How can it be more like Katya? But for now, Milka, welcome. Thank you. If you could just introduce yourself and give us a little bit about your background. Dr. Koupenova:                 Hi, everybody. My name is Milka Koupenova. I am an assistant professor at University of Massachusetts Medical School. Briefly about me, as Cindy mentioned, I did my PhD at Boston University and I studied at that time metabolism in atherosclerosis. Then I had this great opportunity to join this lab in thrombosis that studied these little cell fragments called platelets, which I knew something but not that much about. I joined Dr. Freedman lab as a postdoctoral fellow, and actually my interest evolved to be very much in platelet immunobiology and how platelets may contribute to thrombotic disease during viral infections. Luckily for me, I had two angels that I wanted to be. One of them was Katya Ravid, as you mentioned, and the other one was Dr. Freedman. Both set up a great example of scientists and how to do science in life. Cindy S.H.:                         Wonderful. Excellent. Thank you. I won't lie. I don't know if you feel this way. I definitely feel a little nervous about being a social media editor. I'm talking in a room to a box with a microphone on me and I don't know who's going to be listening. That's also exciting for me too. I get to disseminate all this cool knowledge and share our basic research with this huge audience. What are you most nervous about and excited about? Dr. Koupenova:                 You're doing the podcast, so I don't have to worry about that, that that particular part. I am quite excited actually about everything that's going to surround popularizing the science at Circulation Research. I think in the time that we live in and when social media is a huge part of our life, we definitely need to engage the community, scientific or lay, and communicate our ideas. I'm super excited about the creative part behind how we are going to achieve this via various social medias. Cindy S.H.:                         Can you talk about the platforms that you plan on using? Dr. Koupenova:                 We currently are using Twitter and Facebook. Please follow us on Twitter and Facebook. And we are going to launch Instagram. Find us, follow us, engage us. That will be great. You can always send us messages and like us, retweet whatever you decide. Cindy S.H.:                         Give podcast feedback on Twitter. Nice comments only. Dr. Koupenova:                 We'd like to hear your comments and we'd like to hear what you envision in certain cases when it comes to your Circulation Research, because this is your journal as much as it is ours. We're here for you. In addition to popularize and advertise the wonderful science that we're publishing in Circ Research, we want you to be engaged. We want you to be able to advertise in your own work and to think of it as something that you own and something you need to communicate to the rest of the world. That is one of the things that we want to do. Dr. Koupenova:                 Finally I'm going to echo on what Dr. Freedman said, is we want to attract truly early career and young investigators and help them be involved, help them own their science and help them communicate their ideas. That's pretty much what our social media platform is and we are going to evolve with you. That is perhaps one of the challenges. Cindy S.H.:                         I think one of the most interesting aspects, at least in academia as I see it, is really the role of self-promotion. It's something you're never taught and it's something that you don't really appreciate until you go to that conference. I remember my first conference as a new PI, I was standing there and I'm just like, "Okay, these are all other PIs. How are they all in groups? How does everybody know each other? Why are they all friends already?" It takes a lot of guts and you have to inject yourself. "Hi. I'm Cindy St. Hilaire and I'm new. Please be my friend," essentially, essentially. But it's important and I really liked the fact that when your journal is published you have that little button, share on Twitter, share on Facebook. I think that's really important. It helps you practice that self-promotion and can help really allow you to embrace your extrovert when you know how to. Dr. Koupenova:                 That's exactly what I was going to point out. Scientists or physician scientists, or physician scientists perhaps are a bit better. But as scientists we're very much introverted. But social media gives you a platform that it's not cheesy to popularize and communicate. Then you see those people on conferences and then you have your little group without- Cindy S.H.:                         It's amazing how many Twitter friends I have. "Oh, I met you on Twitter. It's so nice to meet you in real life." Dr. Koupenova:                 It's a new generation. We at Circ Research want to evolve with it. Is that correct, Dr. Freedman? Dr. Freedman:                   That is correct. Thank you very much. Cindy S.H.:                         It's exciting times. I guess maybe this is a question for all of us to talk about, but how do you think we can, number one, attract people to science, attract diverse people to science, and then really keep them in science and how do you think we can use Circ Research and also the social media aspects of Circ Research to do that? Dr. Freedman:                   I think, first of all, people have to see themselves in the journal. The journal, I think the first point I talked about, about being inclusive, inclusive types of people, way people consume science, types of science. We really want people to feel like Circ Research isn't just a journal that puts out scientific papers, but is a forum. It's a forum for them to exchange ideas and it's a forum for them to understand better about their scientific careers. Cindy S.H.:                         Great. Thank you. This has been an amazing first podcast. I'm so happy to share it with the two of you and I'm super excited for this opportunity. Again, Jane, I want to congratulate you on your new position as editor in chief and I can't help but mention as the first female editor in chief. That's a wonderful, wonderful thing. Cindy S.H.:                         You can find us on Twitter. The handle is @CircRes, at C-I-R-C-R-E-S. We're also on Instagram using the same name, C-I-R-C-R-E-S. We hope to hear from you there. Cindy S.H.:                         Thank you for listening. I'm your host, Cindy St. Hilaire, and this is Discover CircRes, your source for the most up-to-date and exciting discoveries in basic cardiovascular research.

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, Associate Editor of Circulation from the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam:                Are NOACs, or non-vitamin K antagonist oral anticoagulants, safe and efficacious in patients with extremely high or very low body weight? Very interesting paper and discussion coming right up. Greg, I hear that you've got a couple of papers you'd like to highlight first. Dr Greg Hundley:             You bet, Carolyn. My two papers today both focus on ventricular dysrhythmia. The first one, from Yuki Komatsu from Tsukuba, Japan, researches the efficacy of catheter ablation of refractory ventricular fibrillation storm after myocardial infarction. VF storm attributed to focally triggered VF after MI is recognized as a distinctive, lethal, arrhythmogenic syndrome that differs from scar mediated monomorphic VT.                                                 This study investigated the acute and long-term outcomes of catheter ablation for the treatment of last resort in a large series of consecutive patients with post-MI VF storm refractory to medical therapies. In the study, investigators enrolled 110 patients averaging about sixty-five years in age. Ninety-two were men, and their average ejection fraction was approximately 31%. VF storm occurred in the acute phase of MI, about four and a half days after MI-onset, during the index hospitalization in about 39% of the patients. It was sub-acute (that is greater than 1 week later) in 44% of patients. It was remote (greater than 6 months later) in 17% of patients. And the focal triggers were found to originate from the scar border zone in 80% of the individuals. Dr Carolyn Lam:                And what did the study show? Dr Greg Hundley:             So Carolyn, during in hospital stay after ablation, VF storm subsided in 84% of patients and overall, 27% of in-hospital deaths occurred. The duration from the VF occurrence to the ablation procedure was associated with in-hospital mortality, with a P-value of 0.008. During follow-up after discharge from the hospital, only one patient developed recurrent VF storm. Of note though, 36% of the patients died, with a median survival of 2.2 years. And the long-term mortality was associated with a low EF (less than 30%), New York Heart Association class greater than 3 Heart Failure, a history of atrial fibrillation or chronic kidney disease.                                                 So in summary Carolyn, the results of this study show that in patients with MI presenting with focally-triggered VF storm, catheter ablation of the culprit triggers is life-saving and appears to be associated with short and long-term freedom from recurrent VF storm. The overall mortality for these patients is associated with the severity of their underlying cardiovascular disease, and those associated co-morbidities.                                                 Now my next paper is from one of our associate editors, Sami Viskin from Tel Aviv University. He's looking at a new form of polymorphic VT. Now as we think about polymorphic VT, I always think about the long QT interval syndromes associated with Torsades de Pointes. We have specific management strategies for those long QT syndromes, but Carolyn, there's a second category of polymorphic VT that's not related to QT prolongation. This second category involves patients without structural heart disease, who have genetic disorders like Brugada or patients that may have experienced hypothermia. There is also a third category of individuals with structural heart disease, during acute ST elevation MI.                                                 What Sami has discovered is there's now a fourth category of non-QT prolongation, which includes those with coronary artery disease but without evidence of ischemia. Dr Carolyn Lam:                So how did they show or find this fourth category? Dr Greg Hundley:             Well, this is a longitudinal cohort that he identified, and they basically followed forty-three individuals who developed polymorphic VT within days of an otherwise uncomplicated MI or coronary revascularization procedure. The in-hospital mortality was 17% with these patients with arrhythmic storm and the patients were treated with quinidine invariably survived to hospital discharge, just like the other categories of non-QT prolongation polymorphic VT.                                                 During long term follow-up of five and a half years, 16% of patients discharged without quinidine developed recurrent polymorphic VT and there were no recurrent arrhythmias in those individuals that were receiving quinidine therapy long term.                                                 So Carolyn, although quinidine therapy is usually considered contraindicated in patients with organic heart disease who develop ventricular arrhythmias, this therapy may be life-saving for patients with coronary disease developed arrhythmic storms due to polymorphic VT. Polymorphic VT storms may be a transient phenomenon. It's unclear for how long quinidine should be continued in these responsive patients. Dr Carolyn Lam:                Wow, neat! Well, for my two papers I'm going to start off with a basic paper and, in fact, a quiz for you this time, Greg! So, what do cilia have to do with the heart? All right, you get to ask me, do you remember what cilia are? Dr Greg Hundley:             Aren't cilia on prokaryotes? I mean, I think of bacteria. Dr Carolyn Lam:                All right, let me set us straight. The primary cilium is a cellular organelle and it's formed by a protrusion of the plasma membrane that functions as a signaling platform in eukaryotic cells and is found in many cells including neurons, pre-adipocytes and kidney tubular cells, where they have been reported to be involved in a variety of cellular functions such as proliferation, differentiation, cell cycle regulation as well as mechano-chemical sensing of diverse stimuli.                                                 Now, the importance of these cilia is highlighted by the role in several diseases, known as ciliopathies. Polycystic kidney disease is one such disorder with, by the way, numerous cardiovascular manifestations. Whereas ciliated cells have been described in the developing heart, a role for primary cilia in the adult heart has not been reported. It was therefore the aim of these authors and those co-corresponding authors Dr Hill from UT Southwestern and Dr Lavandero from University of Chile, who aimed to identify cells in the adult heart harboring a primary cilium and to determine whether these primary cilia play a role in disease-related remodeling. Dr Greg Hundley:             Carolyn, this is so interesting. I had no idea about these cilia. So what did they find? Dr Carolyn Lam:                So, in a series of elegant experiments, these authors identified for the first-time primary cilia in mouse, rats, and human hearts, specifically and exclusively in cardiac fibroblasts. Now these ciliated fibroblasts were enriched in areas of myocardial injury. Transforming Growth Factor beta-1 signaling and SMAD3 activation were impaired in fibroblasts that were depleted of the primary cilium. Extra cellular matrix protein levels and contractile function were also impaired. And in vivo depletion of PC1 inactivated fibroblasts after myocardial infarction impaired the remodeling response. Dr Greg Hundley:             So how do we use this clinically, and what does it mean for us? Dr Carolyn Lam:                These findings point to a pivotal role of cilia and PC1 in disease related pathological cardiac remodeling and suggest that some cardiovascular manifestations of autosomal dominant polycystic kidney disease, for example, derive directly from myocardium autonomous abnormalities. The findings also uncover novel fibrosis regulators and raise the prospect that this pathway may emerge as a target with therapeutic relevance. Dr Greg Hundley:             Wow, very interesting! Dr Carolyn Lam:                Thanks! And the next paper is also very interesting, in dilated cardiomyopathy and providing insights in how specific viral function may be involved in the development of dilated cardiomyopathy. Looking at the Group B enteroviruses, which are a common cause of acute myocarditis and can be a precursor of chronic myocarditis and therefore dilated cardiomyopathy leading to heart transplantation. In fact, enterovirus-induced dilated cardiomyopathy represents a third of idiopathic dilated cardiomyopathy cases.                                                 So these authors, led by corresponding author Dr Andreoletti from University of Reims, Champagne-Ardenne and Dr Semler from University of California, performed deep sequencing of viral RNA from cardiac tissue from patients with enterovirus related end stage dilated cardiomyopathy and then trans-factored viral RNA clones, mimicking the viral genomes found in patient tissues into primary human cardiac cells to assess their replication activities and impact on cardiomyocyte function.                                                 They found that the major persistent viral forms are composed of B-type enteroviruses harboring 5' terminal deletion in their genomic RNAs. These viruses alone, or associated with full length populations of helper RNAs, could impair cardiomyocyte function by viral enterovirus proteinase 2A activities in these enterovirus-related dilated cardiomyopathy cases. Dr Greg Hundley:             Very interesting, Carolyn. So what are the clinical implications of this viral infection of the heart? Dr Carolyn Lam:                Well, the findings seem to imply that it would be important for us to develop specific inhibitors of enterovirus proteinase 2A activity that might prevent viral replication and inhibit the shut-off of host cell translation as well as the disruption of dystrophin.                                                 Furthermore, in early diagnosed enterovirus induced dilated cardiomyopathy, the use of such protease inhibitors could potentially decrease and stop the chronic pathological process of dilated cardiomyopathy and therefore reduce the need for heart transplantation in this end-stage. Very interesting, but requires more work.                                                 So, that wraps up our summaries Greg. Shall we move to our feature discussion? Dr Greg Hundley:             Absolutely. Dr Greg Hundley:             Today we have Renato Lopes from Duke University in Durham, North Carolina and Brian Olshansky, Professor Emeritus from Iowa now in clinical practice in Waterloo and Mason City, Iowa. We're going to talk about our non-vitamin K oral antagonists, or NOACs, safe and efficacious in patients in extremely high (greater than 120 kg) or extremely low (less than 60kg) of body weight.                                                 Renato, welcome to our podcast in Circulation on the Run. Can you give us a little overview of your study, why you performed it and what results did you experience? Dr Renato Lopes:              The idea behind this study was to provide more data into the use of NOACs in these extreme body weight patients, where we don't have a lot of information. Some guidelines actually caution against the use of NOACs in patients with extreme body weight because of the lack of data.                                                 We had the opportunity to look at the Aristotle database, which was a large, randomized trial comparing apixaban versus warfarin for patients with atrial fibrillation, over 18 000 patients. We took advantage of this database to try to look at the extreme body weight and how those patients at weight more than 120 kg, more than 140 kg and less than 60 kg, performed in terms of the treatment effect of apixaban versus warfarin. This was the rational, to try to provide more data so people could gain additional confidence in using apixaban in clinical practice in those extreme body weight patients.                                                 What we showed was, in general the treatment effect of apixaban versus warfarin for the efficacy outcomes CHOKE, systemic embolism and all cause death and myocardial infarction was very consistent across the weight spectrum and preserved. Apixaban was superior to warfarin and this was consistent regardless of the weight category. For the low body weight patients less than 60 kg, we also found that apixaban results in terms if efficacy was preserved.                                                 So, going out to the bleeding and safety endpoints, apixaban was safer than warfarin across different spectrums of weight. Surprisingly, in patients less than 60 kg we saw an even greater relative risk reduction in bleeding, in patients treated with apixaban compared to warfarin. The main message was for efficacy, apixaban was better than warfarin - the same results as the Aristotle main trial. For bleeding and safety endpoints, we also saw the same results and consistent results with apixaban- in particular with patients below 60 kg, which is always a concern that people might have in clinical practice. It seems that apixaban was even safer with an even greater treatment effect. Dr Greg Hundley:             Very nice. Can you tell us a little bit about some of the sites where you enrolled patients and did you identify any variation in age, sex or region specific factors? Were there any differences in your findings related to race? Dr Renato Lopes:              That is a very interesting question because we know that these variables play an important role in body weight. We enrolled patients from thirty-nine countries in Aristotle, in over a thousand sites all over the world. Interestingly, I can tell you that the heaviest weight we had in our study was 205 kg, a patient from the United States. The lightest weight that we had was 39 kg, from the Philippines. You lose trading the variation that regions of the world can play out and how patients can perform. We haven't seen any major difference in these analogies. There were prior analogies that look at different BMIs, and we know that the treatment effect might be attenuated depending on race and sex. In this analogy, we did not find any significant difference according to race, region of the world or even sex. Dr Greg Hundley:             Just getting back to your body weight measurement, you mentioned percentage of individuals were above 120 kg and briefly mentioned some were above 140 kg. What percentage of your study cohort was that extra-large size, above 140 kg? Do you think more work needs to be done in that area or do you think the results were sufficient for that very heavy body weight? Dr Renato Lopes:              This is a very important question. If we look at the breakdown, we had about 11% of the entire trial in the low spectrum of weight, less than 60 kg in weight - almost 2000 patients. A good number of patients. In extreme weight more than 120, we have about 980 patients. That was 5.5% of the overall trial. When you look at greater than 140 kg, we had 258 patients, 1.4% of the overall trial population and about 25% of this category greater than 120.                                                 I think as we start getting greater than 140 kg, we had 258 patients. It is not a large number of patients. It is some information and it is good to have some data on these patients. Before that, we had no data on apixaban in this level of weight. What we are seeing is that above 140 kg, the death rate are very low. There is a trend to better bleeding endpoints and better bleeding profile with apixaban, similar to what we have seen in the entire spectrum of weight when we look at weight as a continuous variable. We also saw that trend in patients greater than 140 kg for bleeding. This is reassuring. I don't think we can say it is definitive, it is only 260 patients that we are talking about.                                                 It is reassuring that we now have data in patients more than 140 and up to 205 kg, and we didn't seem to see any major concern or any difference in the curves in terms of the direction of efficacy and safety of apixaban. For the majority of patients it is reassuring and gives us extra confidence that the dose we use in clinical practice five milligrams twice daily should also work in those heavy weight and the heaviest body weight patients. Dr Greg Hundley:             Very good. Brian you've done an excellent editorial and I wonder if you could help us put this study in perspective with what we know about NOACs and managing patients with atrial fibrillation? Dr Brian Olshansky:         It really is a fascinating study. Obesity is as growing problem for us here in the mid-west and probably throughout the world. It effects a variety of things including drug pharmakinetics, volume of distribution, drug clearance etc. So knowing how NOACs work at the extremes of body weight, either the massively obese or the vanishingly frail, it becomes important to understand the safety and efficacy of the use of NOACs in these individuals. There are guidelines that caution us against use of NOACs at extremes of body weight, particularly those patients who are over the 120 kg mark. The one point I would like to make is, at least here in the mid-west, 120 kg is becoming almost the norm. We are having people that are becomingly massively obese and this is really the question then in my mind, is what to do with those patients who are over 140 kg or even way more than that. This gets to points that I would like to make about some the issues we need to consider about this study and where we are with our understanding about the use of NOACs in the extremes of body weight.                                                 One thing to keep in mind is, in this analysis, this was a retrospective group analysis. That is one important point. We don't have prospective data that look at an entire large population, a very frail, a very low body weight population.                                                 Another issue is that weight is not a static measure. We only have assessment at the baseline. Variability in weight or body mass index may be important in terms of its relationship to the development of atrial fibrillation and sequelae. The other issue here to consider is that there are comorbidities that are associated with those who are at the extremes of body weight and there was a significant variation in this study in age composition, sex dominance, the region of enrollment, the presence of comorbidities between the different weight groups that could contribute to results we have seen. Those with low body weight had more comorbidities and a higher mean CHADSVASC score, and had the biggest difference between apixaban and warfarin.                                                 We have quite a bit to learn about how to understand these data, and when we consider the individuals who are over 140 kg, indeed there are concerns about the volume of distribution of a NOAC and its efficacy. We would like to rely on this data. The problem is that the number of individuals that are a part of this retrospective analysis at the very high body weight and very low body weights was a rather small number and so to project from that number, what we should do with all of our patients becomes somewhat of a concern.                                                 Although these are interesting and provocative data, what we really need is to have some well-designed large prospective randomized controlled trials that specifically address those individuals at the extremes of body weight because this is becoming more and more of a problem as time goes on. We are seeing more individuals that are at the extremes of body weight. While I have not specifically noticed a difference in my own clinical practice, what we need is a better understanding about the dosing of and potential risks and benefits of the NOACs for the extremes of body weight. Dr Greg Hundley:             On behalf of Carolyn and myself, we really appreciate you listening. Have a great week. We look forward to seeing you next week. Dr Carolyn Lam                  This program is Copyright American Heart Association 2019.  

Jane Ferguson:                 Hello, welcome to Getting Personal: Omics of the Heart. This is podcast Episode 15 from April 2018. I'm Jane Ferguson, an Assistant Professor of Medicine at Vanderbilt University Medical Center, and this podcast is brought to you by Circulation Genomic and Precision Medicine and the AHA Council on Genomic and Precision Medicine.                                                 As usual, we have a great lineup of papers in Circ Genomic and Precision Medicine this month. The first is actually the subject of our interview this month. Sony Tuteja talked to Craig Lee from the University of North Carolina about his manuscript entitled, "Clinical Outcomes and Sustainability of Using CYP2C19 Genotype Guided Antiplatelet Therapy After Percutaneous Coronary Intervention." This manuscript investigated the use of pharmacogenomics to improve treatment after PCI, and you can hear a lot more about it directly from the first author later in the podcast.                                                 Our next manuscript also used pharmacogenomics approaches to look for snips associated with plasma renin activity and to assess the effect of top snips with blood pressure response to atenolol and hydrochlorothiazide. The first and last authors are Caitrin McDonough and Julie Johnson from the University of Florida. And their manuscript is entitled, "Genetic Variants Influencing Plasma Renin Activity in Hypertensive Patients from the Pharmacogenomic Evaluation of Antihypertensive Response," or PEAR study. They find that snips in the SNNTXNDC11 gene region associate with higher baseline plasma renin activity in their sample of over 700 subjects and with a smaller systolic blood pressure reduction to hydrochlorothiazide. Variation in the region may act through modulation of TXNDC11 gene expression. They also identified several other candidate genes of interest. These new candidates may allow for precision medicine approach to selection of hypertensive treatment and further study the mechanisms may reveal novel biology on blood pressure response to pharmacological treatment.                                                 Next up is a manuscript by Deirdre Tobias and colleagues entitled, "Circulating Branch Chain Amino Acids and Incident Cardiovascular Disease in a Prospective Cohort of U.S. Women." I actually had the chance to talk to Deirdre about her research last month. So check out the March podcast, Episode 14, to hear more from Dr. Tobias about this study.                                                 A study of hypertrophic cardiomyopathy from Hannah [inaudible 00:02:36] and Michelle Michels and colleagues from the Erasmus Medical Center in the Netherlands assessed the effects of genetic screening in family members of patients with a known hypertrophic cardiomyopathy mutation. In their manuscript entitled, "Outcomes of Contemporary Family Screening and Hypertrophic Cardiomyopathy," they described their study which assessed cascade screening in 777 relatives of 209 probans between 1985 and 2016. Genetic and clinical screening resulted in a diagnosis of HCM in 30% of family members at the time of testing. An additional 16% of family members developed HCM over seven years of follow up. Of the 43% of family members who were genotype positive, 37% were ultimately diagnosed with HCM. There was no difference in survival between genotype positive and genotype negative family members or with relatives who did not undergo genetic testing.                                                 There are genetic considerations that are unique to the ancestral composition of the Netherlands with a high proportion of individuals with a founder mutation, so the proportion of probans with identified mutations is higher than in other reported studies. This paper demonstrates the potential benefit of genetic screening in family members, which can identify individuals who should undergo intensive screening, and at the same time reduce concerns for family members who are genotype negative. However, the classification of the pathogenicity of variants and understanding variable penetrance remains a challenge.                                                 A manuscript entitled, "Exome Sequencing in Children with Pulmonary Arterial Hypertension Demonstrates Differences Compared to Adults." From Na Zhu, Claudia Gonzaga-Jauregui, Carrie Welch, Wendy Chung, and colleagues from Columbia University, ask the question whether there were differences in the genetic mutations responsible for early onset pulmonary arterial hypertension, or PAH, in a pediatric sample compared with adult onset disease. While some mutations, particularly in BMPR2 appear to be similar in the pediatric and adult samples there were significantly more mutations in TBX4 in the children compared with adults.                                                 Further, children were more likely to have de novo mutations identified through exam sequencing that were predicted missense variants. Given the additional complications associated with pediatric onset of PAH, understanding the genetic differences in this population is an important step towards identifying novel genes and mechanisms which could guide future therapeutic development.                                                 Our next manuscript authored by Iisan Kadhen, Carolyn Macdonald, Mark Lindsay, and colleagues from Harvard Medical School is entitled, "Prospective Cardiovascular Genetics Evaluation in Spontaneous Coronary Artery Dissection," or SCAD. They genotyped individuals with SCAD to find out the genetic contribution to the disease. Of the patients for whom genetic testing was performed, six of them were 8.2%. Identifiable mutations in genes known to be involved in vascular disease, including COL3A1, LMX1B, PKD1, and SMAD3. These individuals were significantly younger at the time of their first SCAD event compared to patients with no identifiable mutation. Given the relatively higher rate of mutations identified in this sample, there may be a rationale to conduct genetic testing in all individuals presenting with SCAD, particularly in younger individuals.                                                 Shiu Lun Au Yeung, Maria-Carolina Borges, and Debbie Lawlor, from the University of Hong Kong and the University of Bristol, set out to find out if reduced lung function is causal in coronary artery disease. As reported in their manuscript, entitled "The Association of Genetic Instrumental Variables for Lung Function on Coronary Artery Disease Risk, A 2-Sample Mendelian Randomization Study," they used a Mendelian Randomization approach to assess causal relationships between two measures of lung function. Forced expiratory volume in one second, and forced vital capacity on CAD. Genetic predictors of increased forced expiratory volume were associated with lower risk of CAD. While there was a similar association with forced vital capacity, this was attenuated in sensitivity analyses. Overall, the data suggests that higher forced expiratory volume may independently protect against CAD. However, the mechanisms remain unclear.                                                 Finally, the April issue also contains a white paper from Kiran Musunuru, Xiao-zhong Luo, and colleagues entitled, "Functional Assays to Screen and Dissect Genomic Hits, Doubling Down on the National Investment in Genomic Research." This paper lays out strategies to followup on findings from high-throughput genomic analyses, including the use of novel technologies, assays, and model systems that can help to effectively translate big data findings and capitalize on previous investment in genomic discovery.                                                 To see the latest issue of Circulation Genomic and Precision Medicine, and to access all the papers we talked about and to browse previous issues, go to "circgenetics.ahajournals.org." Sony Tuteja:                       Hello, my name is Sony Tuteja, I'm an assistant Professor of Medicine at the University of Pennsylvania in Philadelphia, I'm also an early career member of the American Heart Association Council on Genomic and Precision Medicine. Today I'm joined by Dr. Craig Lee, an associate Professor of Pharmacy at the University of North Carolina School of Pharmacy. Dr. Lee is a first author of an article published in April 2018 issue of Circulation Genomic and Precision Medicine entitled, "Clinical Outcomes and Sustainability of Using CYP2C19 Genotype Guided Anti-Platelet Therapy After Percutaneous Coronary Intervention." Welcome Dr. Lee, and thank you for joining me today. Craig Lee:                            Thanks for having me. Sony Tuteja:                       First let me just say congratulations on spearheading such impactful work on the implementation of CYP2C19 pharmacogenetic testing. Craig Lee:                            Thanks, this has been a very complicated project, but a lot of fun. Sony Tuteja:                       Great. So I think some of our listeners may have not had time to read your paper yet so I was wondering if you could provide a brief overview of the paper and what the study was about. Craig Lee:                            Sure. Although it's been widely described that loss of function polymorphisms in the drug metabolizing enzyme, CYP2C19, which is responsible for the bio-activation of the antiplatelet drug clopidogrel, impairs its effectiveness, there remains considerable debate and uncertainties surrounding whether CYP2C19 genetic testing should be used clinically for guiding antiplatelet therapy in percutaneous coronary intervention, or PCI patients. As the evidence base is expanded, an increasing number of institutions are seeking to implement CYP2C19 genetic testing despite limited data on the use and impact of using this genetic testing to guide antiplatelet therapy selection following PCI in real world clinical settings.                                                 UNC was an early adopter for CYP2C19 genotype-guided antiplatelet therapy in high-risk PCI patients. Our algorithm recommends that patients carrying one or two loss of function alleles in CYP2C19 be prescribed an alternative antiplatelet therapy such as prasugrel or ticagrelor. Our algorithm was implemented back in the summer of 2012, under our then-director of the Catheterization Laboratory, and now Chief of Cardiology, Dr. Rick Stouffer. We conducted the study to better understand the feasibility, sustainability, and clinical impact of using CYP2C19 genetic testing to optimize antiplatelet therapy selection in PCI patients in real-world clinical practice.                                                 Basically what we did was following the implementation of our algorithm in the summer of 2012, we've been retrospectively collecting data from all patients that come through our Cath lab that undergo a PCI. We collect information on their clinical characteristics, whether or not they underwent CYP2C19 genetic testing, what antiplatelet therapy they were prescribed when they were in the hospital at discharge and over the course of followup, and more recently we've been assessing clinical outcomes, both ischemic outcomes and bleeding outcomes. The data presented in our paper described the algorithm's use at our institution over the first two years following its implementation from 2012 to 2014 with one year of followup data. Since we do about 600 PCI procedures per year on our Cath lab, the study population is just under 1200 patients.                                                 Our main findings were that CYP2C19 genotypes were frequently ordered, efficiently returned, and routinely used to guide antiplatelet therapy selection after PCI over this two year period. However, we also observed that the frequency of genotype testing and frequency of using alternative therapy such as prasugrel or ticagrelor in the patients that carried CYP2C19 loss of function alleles fluctuated over time. We also observed that use of clopidogrel in patients that were tested, but carried either one or two copies of a CYP2C19 loss of function allele was associated with a significantly higher risk of experiencing a major ischemic cardiovascular event compared to use of alternative therapy. These risks were particularly evident in the highest risk patients, and largely driven by patients who carry only one copy of the loss of function allele, the so-called intermediate metabolizers.                                                 Our primary takeaway from this analysis is that implementing a genotype-guided antiplatelet therapy algorithm is feasible, sustainable, and associated with better clinical outcomes in a real-world clinical settling, but challenging to maintain at a consistently high level over time. Sony Tuteja:                       Great. I know it's always challenging to implement new work flow and new testing into the clinical setting. Can you describe how the algorithm was incorporated in the cardiologist workflow to minimize disruption? Craig Lee:                            Absolutely. This algorithm was spearheaded by our interventional cardiologists with the support of our clinical pharmacy specialists and pathology laboratory. They key element to our success is that we have the capacity to do the genotype testing in our molecular pathology lab on site. Dr. Karen Weck is the director of that laboratory and is a coauthor on our paper. Since the prescribing decision for antiplatelet occurs in a highly specialized clinical setting, we have all the pieces in place to do this in-house at UNC, which seems to make things very efficient.                                                 There really wasn't very much disruption in the workflow given that the testing is done on-site and the test seems to be treated like another laboratory test that's done, which is really the ultimate goal of pharmacogenomics. We don't currently actually have clinical decision support built into our electronic health record, so the reason we could actually get this off the ground was because of the substantial collaboration between our physicians, pharmacists, and pathology lab.                                                 But one of the things we learned through this experience, which is described in the paper, is that there are fluctuations in the use of the genetic testing to guide prescribing over time that we believe could be remedied by developing more automated clinical decision support, to help make things a little bit more efficient for the clinicians. But at the start of it, it was really just a will to do it, which was really exciting to observe. Sony Tuteja:                       Absolutely. That's exciting that everybody was on board with this project. What do you think were the most challenging aspects of the implementation? Craig Lee:                            That's a great question, and one that often comes up. I think that the education on the front end is really, really important. It needs to recur as the implementation spans over a period of time. For example, there's turnover in the interventional cardiology fellows every summer as well as occasional turnover of attending physicians and clinical pharmacy specialists. As individuals come and go into the clinical environment, it is important that they understand how the algorithm works, and how it can be applied in practice. And this is accomplished by recurring education and communication.                                                 The other thing that's been a challenge is turnaround time. Even though our molecular pathology lab typically turns tests around within one day of a PCI procedure, if the test result isn't available or the antiplatelet therapy isn't changed in response to the genetic test before the patient is discharged from the hospital, we found that it can be challenging to followup on the result before the next encounter. Typically, if a change in medication needs to occur after discharge and prior to the first followup clinic visit, the communication piece has proven to be very important. It's not an insurmountable barrier, but one we observe that created one additional challenge. Other institutions around the country that are doing this have expressed similar things. Sony Tuteja:                       You showed in your study that during the middle of the implementation there was a decline in testing. What do you think were the major reasons that led to decrease in testing? Craig Lee:                            Yeah, that's a great question. We're not sure. We didn't collect information prospectively, and more specifically, we did not survey the physicians in terms of why they ordered the test. But we believe, just based on anecdotal experience and talking about this with everyone, there was this big surge of momentum, with the initial implementation, and as the practice evolved there was just sort-of a settling of individuals in terms of, I think, the practice patterns.                                                 Overall, the test was ordered and over 70% of PCI patients, an alternative therapy was prescribed and approximately 70% a loss of function allele carriers. These numbers exceeded 80% early on which was higher than we expected. They dropped down to about 60%, which is still a pretty high utilization rate when you compare to other institutions that have implemented. After some educational efforts, the testing rates and use of alternative therapy and loss of function allele carriers began to increase again over the last six months. Sony Tuteja:                       Yeah I was just gonna ask, since the study is completed, have you taken any further steps to maintain the frequency of the testing at the high level that you initially started with? Craig Lee:                            Yeah, so again recurring education has been really important particularly with interventional cardiology fellows, since they're the ones that really execute this in terms of ordering the tests and working with the clinical pharmacy specialists. And as I mentioned, we're in the process of developing clinical decision support to help make this a little bit easier on the prescribers. When a test result is available, we believe this will make it a little easier for the result to be more readily available for the clinical decision. Sony Tuteja:                       Yeah I think the CDS tools will be key to have more compliance with the results in adherence to the test results. I'm just curious, who pays for the genotype tests at your center and are you billing for these tests? Craig Lee:                            Yes. We're billing for these tests as part of routine clinical care. Sony Tuteja:                       Great, and you've had good success with reimbursement? Craig Lee:                            As far as we can tell, yes. Sony Tuteja:                       That's great to hear. I think that will really incentivize other centers to pursue similar lines of testing. So what do you think are the broader implications for implementing genetically guided care for other drugs? Craig Lee:                            Yeah, I think that it's interdisciplinary collaboration. Communication is really important among physicians, clinical pathologists, and clinical pharmacists. We found that this has been essential to success of the program here at UNC with this one gene drug pair. And again, this is fueled by a spirit of collaboration and will for our clinicians to work together to optimize patient care. And really, I think clinical pharmacists are uniquely positioned to help make this happen. Clinical pharmacists are uniquely positioned to interpret pharmacogenomic test results, provide medication recommendations, as well as counsel patients on how to interpret the tests and why the prescribing decision is being made. Our clinical pharmacists at UNC are fantastic and have really embraced this. They've shown that pharmacogenomics can be an important part of medication therapy management.                                                 Although implementation of pharmacogenomics testing is clearly a challenge, it is now part of the routine in our Cath lab and in our cardiology services. And again, that's been really exciting to observe. I also think this experience provides a foundation in an example for other pharmacogenomic implementations to occur at our institution. Sony Tuteja:                       That's great, it's so nice to hear about the team working together to get this accomplished. What has been the patient response to the testing? How have they responded to receiving genetic test results? Craig Lee:                            We think it has been overall positive. And again, it's now part of the workup in terms of providing the best possible care for the patient given the evidence that we have. And so again, since it's part of the clinical work flow, there's not a separate research consent that's done. The testing is part of the consent to the procedure. Sony Tuteja:                       Well great, that's all the questions I have for you today. Do you have any final thoughts you wanna share with our listeners? Craig Lee:                            No, other than just a thank you again for having me in for talking about our paper. And I guess, I would just urge those that are out there that are either planning to do this or doing this, to collect data. It's really important to evaluate the practice, evaluate the frequency of testing, the frequency of prescribing decisions being altered by the testing, and trying to understand what the barriers are. And if possible, evaluate clinical outcomes.                                                 You know, we started this study under the umbrella of continuous quality improvement and it really has taught us a lot. I think it has helped optimize how the algorithm is used, and as other centers around the country have been doing this, it provided a basis to collaborate and really evaluate the impact on clinical outcomes, which is really the question that is on everybody's minds. And as the evidence base expands, I think there will be a lot more comfort with doing these things, but we should always strive to generate the evidence we need to assure that we're making the right decisions in practice. Sony Tuteja:                       Absolutely, I think that outcomes piece will be critical to getting this in the mainstream. Well I'd like to thank you for your time today, it was a pleasure speaking to you and once again, congratulations. Craig Lee:                            Thanks. Jane Ferguson:                 That's all for this month. As a reminder you can follow us on Twitter, @Circ_Gen or connect with us on Facebook. Thanks for listening, and I look forward to bringing you more on genomics and precision medicine of the heart next month.  

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.                                                 Today's feature paper is going to cause us to rethink the way we prognosticate patients with pulmonary arterial hypertension following their initial management. Think you know the hemodynamic variables? Well, stay tuned for this discussion coming right up after these summaries:                                                 Our first original paper this week shows for the first time the predictive value of coronary artery calcification progression for coronary and cardiovascular events in a population base study. Authors Dr. Erbel and Lehmann from University Hospital Essen in Germany and their colleagues evaluated several progression algorithms between CTs performed at baseline and after a mean of five years for the risk prediction of coronary and cardiovascular events in a population base cohort of more than 3,200 participants initially free from cardiovascular disease.                                                 The authors found that coronary artery calcification progression added some predictive value to the baseline CT and risk assessment, and even when the five-year risk factors were taken into account. However, the progression yielded no additional benefit when the five-year coronary artery calcification results were taken into account instead of the baseline coronary artery calcification results.                                                 Double zero coronary artery calcification scans in a five-year interval meant an excellent prognosis, which was better than the prognosis for incident coronary artery calcification after five years. Thus, the authors concluded that sophisticated coronary artery calcification progression algorithms may be unnecessary and clinicians can instead rely on the most recent risk and coronary artery calcification assessment.                                                 The next paper demonstrates for the first time cell-specific effects of Smad3 signaling in the infarcted myocardium. Now, in the infarcted heart, Smad3 signaling is known to be activated in both cardiomyocytes and the interstitial cells. In the current paper, co-first authors, Doctors Kong and Shinde, corresponding author Dr. Frangogiannis from Albert Einstein College of Medicine in New York, and their colleagues hypothesized that cell-specific actions of Smad3 may regulate, repair, and remodeling in the infarcted myocardium.                                                 In order to dissect the cell-specific Smad3 actions in myocardial infarction, these authors generated mice with Smad3 loss specifically in activated fibroblasts or in cardiomyocytes. They found that fibroblast-specific Smad3 activation played a critical role in repair following myocardial infarction by restraining fibroblast proliferation and contributing to scar organization by stimulating integrin synthesis.                                                 On the other hand, cardiomyocyte-specific Smad3 signaling did not affect acute ischemic injury, but triggered nitrosative stress and induced matrix metalloproteinase expression in the remodeling myocardium, thereby promoting cardiomyocyte death and contributing to systolic dysfunction.                                                 In summary therefore, these authors demonstrated the cellular specificity of Smad3-dependent actions that stimulate distinct cellular responses in fibroblasts versus cardiomyocytes in the healing myocardial infarction. The implications are that nonspecific therapeutic targeting of Smad3 signaling in pathologic conditions may interfere with both detrimental and beneficial actions. On the other hand, design of interventions with specific cellular targets may be needed for the development of safe and effective therapies.                                                 Good news from the next paper! Genetically predetermined high blood pressure and its complications may be offset by healthy lifestyle. Well, at least, to some extent. First author, Dr. Pazoki, co-corresponding authors Dr. Elliott from Imperial College London and Dr. Tzoulaki from University of Ioannina in Greece aimed to investigate the extent to which lifestyle factors could offset the effect of an adverse blood pressure genetic profile as well as its effects on cardiovascular disease risk.                                                 To do this, they constructed a genetic risk score for high blood pressure using 314 published blood pressure loci in more than 277,000 individuals without previous cardiovascular disease from the UK Biobank study. They scored participants according to their lifestyle factors including body mass index, healthy diet, sedentary lifestyle, alcohol consumption, smoking, and urinary sodium excretion levels measured at recruitment. They examined the association between tertiles of genetic risk and tertiles of lifestyle score with blood pressure levels and incident cardiovascular disease.                                                 They found that adherence to a healthy lifestyle was associated with lower blood pressure regardless of the underlying blood pressure genetic risk. Furthermore, adherence to a healthy lifestyle was also associated with lower risk of myocardial infarction, stroke, and the composite cardiovascular disease at all levels of underlying blood pressure genetic risk. Healthy compared to unhealthy lifestyle showed a 30%, 31%, and 33% lower risk of cardiovascular disease respectively among participants at low, middle, and high genetic risk groups. Thus, these results strongly support population-wide efforts to lower blood pressure and subsequent cardiovascular disease risk through lifestyle modification.                                                 The final paper is an aggregate report from two large randomized trials, which demonstrate for the first time that more potent antiplatelet therapy further lowers venous thromboembolism risk relative to aspirin alone. First author Dr. Cavallari, corresponding author Dr. Bonaca, and colleagues from the TIMI Study Group in the Brigham and Women's Hospital ascertained and characterized symptomatic venous thromboembolism events in more than 47,600 patients randomized in the TRA 2°P-TIMI 50 and PEGASUS-TIMI 54 trials. They evaluated risk of symptomatic venous thromboembolism over time, independent risk factors for venous thromboembolism, and the efficacy of more intensive antiplatelet strategies at reducing venous thromboembolism risk.                                                 They found that the rate of venous thromboembolism in patients with atherosclerosis was 0.3% per year while on treatment with at least one antiplatelet agent. This risk increased independently with the number of symptomatic vascular territories. Furthermore, more intensive antiplatelet therapy with Vorapaxar and Ticagrelor in this case reduced the risk of venous thromboembolism.                                                 These data suggested a relationship between atherosclerosis burden and venous thromboembolism risk. The data also support the inclusion of venous thromboembolism as a prospective endpoint in long-term secondary prevention trials evaluating the risks versus benefits of antiplatelet therapies in patients with atherosclerosis.                                                 Well, that wraps it up for our summaries. Now for our feature discussion.                                                 For our feature discussion today, we are talking about pulmonary arterial hypertension. We've learned so much from registries about prognostication of pulmonary arterial hypertension at the time of diagnosis. But these registries have only provided limited insight into the impact of therapies on long-term outcomes and how we're supposed to use variables after initiation of therapy to determine prognosis.                                                 Well, that gap is being filled by today's paper in circulation. I'm so pleased to have the first and corresponding author with us, Dr. Jason Weatherald from University of Calgary, as well as Dr. Kelly Chin, associate editor from UT Southwestern, to discuss this very important paper.                                                 Jason, congratulations on this paper. Could you tell us a bit more about what you did and why you did it, and what's exciting about what you found? Dr. Jason Weatherald:   This is a study that started during my research fellowship last year when I was spending time in Paris with the group of Professor Olivier Sitbon and Marc Humbert. We started this study based on some other recent papers showing the importance of pulmonary arterial compliance, and some smaller studies that emphasized the importance of hemodynamic variables after treatment initiation and the prognostic importance of that. We wanted to look at the relative importance of pulmonary arterial compliance as well as the stroke volume in the cardiac index in newly diagnosed patients.                                                 We looked at a 10-year cohort from the French registry of patients who had right heart catheterizations at baseline and then after treatment initiation. We looked at prognostic variables, both at baseline and at the first follow-up after initial treatment. The interesting result is that we found that actually pulmonary arterial compliance is not the most important prognostic variable, but it seemed that the stroke volume index, which was calculated from the cardiac index and the heart rate, was the most significant independent predictor of long-term survival from the hemodynamic perspective. Dr. Carolyn Lam:               Kelly, could you help point out why this is so important in clinical practice? You see a lot of these patients. In what way did this paper make you think differently about them? Dr. Kelly Chin:                    I think there's a couple different areas that really struck me. The first one was, as you mentioned in the introduction, the importance of post treatment values versus baseline values. This is not to say that the baseline values aren't important because it does still associate with survival and it's very important when choosing therapy, but as PAH therapies have become more effective, we would hope to see that the baseline severity matters less and that, indeed, seems to be what we're seeing here. That also reinforces the importance of serial reassessment to see how your patient is doing and make further decisions for therapy.                                                 The second key finding, I think, is what Jason was just talking about with which hemodynamic measures do we really want to be keeping a close eye on? Here's where, in the stepwise analysis, they found that the right atrial pressure and then, the surprising one, the stroke volume index were the key measures that were associated.                                                 Interestingly, cardiac index fell out of that model. That isn't to say that cardiac index wasn't associated with outcome. It was a predictor in the univariate analysis. But I think when you step back and you think about the comparison between those two, if you have a patient who's maintaining their cardiac index only by becoming tachycardic, they're probably not doing nearly as well as a patient who has a normal heart rate and a normal stroke volume index.                                                 I think this really struck me as something, "Hey, when I'm in the cath lab, I probably need to be thinking about this and reporting it out, so everybody's seeing it right there on the report", which is not something we've been doing. Dr. Carolyn Lam:               Thanks Kelly. That makes so much sense. What I really appreciated about the paper as well is that they gave us practical thresholds through their receiver operating characteristic analyses. Just for everyone to know, the threshold value for stroke volume index was 38 mils per minute per meter square, right? And the right atrial pressure threshold was 9 mils of mercury. These are sort of very important, 38 and 9, and practical to keep in mind. Really appreciate that Jason.                                                 The other thing that struck me is these are just very much saying that right ventricular function is important. Is it not, Jason? Dr. Jason Weatherald:   Yeah, I agree. I think that's one of the interesting insights from the study is that we focused mostly on the cardiac index, but it can be misleading in certain patients like Kelly said who perhaps do respond to therapy by increasing the cardiac index but predominantly through increased heart rate. That can be somewhat misleading if you don't really step back and look at it.                                 What I found interesting, too, is that when we looked at subgroups of patients who, in the clinic, you generally think are low risk patients who had good six-minute walk distance, very few symptoms NYHA functional class I or II, and had a cardiac index above the current recommended target of 2.5, that there was almost a third of patients with a low stroke volume index in that category and that seemed to be the majority of patients who died over long-term follow-up within five years.                                                   I think that's really telling about the importance of right ventricular function and just looking at the cardiac index itself can perhaps mislead you if you don't take all of those other factors into consideration. Dr. Carolyn Lam:               Yeah, that's just such a great point and important. That even those classified that we would not have picked up as high risk are the usual measures that we look at. If you look at stroke volume index, they still distinguish those who do better than those who do worse. This is something that was also highlighted, I think, in the accompanying editorial, Kelly, that you invited by Lewis Rubin from New York.                                                 Kelly, what do you think are the real take home messages from this? Dr. Kelly Chin:                    I think he does make a big point that the functional status of the right ventricle is a primary goal of therapy, and that we should definitely be paying attention to it and that there's more than one way to do this. There's the hemodynamic measurements, there's also exercise capacity and functional class, which really do associate with how well the right heart is functioning, both at rest and exercise. I think he also comes back to the serial measurements and the importance of reassessment. Dr. Carolyn Lam:               Yeah, as you had also so elegantly summarized earlier. But, a quick question to both of you. What do we do now about other measures of right heart function? I mean, magnetic resonance imaging seems to be used increasingly for this. Where does this fall in? And what does this say about the routine clinical parameters that we usually look at, like six-minute walk? Jason? Dr. Jason Weatherald:   I have a couple points on that. Number one, I fully agree and our results are really in keeping with the previous smaller studies looking at cardiac magnetic resonance and showing the importance of the stroke volume on imaging. From personal experience, although MR is wonderful, there's a good population of patients who don't really tolerate MR, especially for serial measurements, and there's other contraindications, so I think hemodynamics will continue to fill an important role and are still useful in the patient where you can't figure out exactly what's going on and why they're getting worse.                                                 At this point, I think it's complementary and certainly I think there's some centers in many countries that don't have cardiac MR widely accessible, especially for serial follow-ups, so I think they're really complementary and that our results support imaging studies.                                                 I would say the next thing about the study is that, in the multi variable models that exercise distance, the six-minute walk distance and functional capacity remained independent predictors, so I think, it just highlights the importance and the robustness of these measures, even though NYHA functional class is subjective, it remains a very powerful predictor at baseline and during follow-up. To me, it speaks to the importance of looking at multiple parameters and coming to a multidimensional assessment of risk and PAH and not focusing on one particular variable for making decisions in the clinic. Dr. Kelly Chin:                    I definitely agree with the multidimensional look at a patient function and heart and catheterization. What I was going to say was I also liked, Jason, the use of "complementary" when talking about catheterization and MRI. I see MRI filling a similar niche to echo for many patients. I think if you get an echo and it looks great, heart size is good, heart function is good, I don't see a whole lot of reason to add an MRI, too. We're always routinely doing catheterizations, at least early post treatment, to reassess.                                                 But I do see a role for MRI in some of our patients who are doing not well at all, but we're not quite sure if they're doing poorly enough that it's time for transplant, and I'm trying to decide if the RV is growing or not. It's clearly big, but is it getting bigger each six months that we're looking at it? Sometimes MRI just seems to provide so much more precision than we can get with echo and certainly you're not getting any of those types of measures off of your catheterization. Dr. Carolyn Lam:               Maybe one last question Jason. It's so interesting. What is the future? What are the gaps that you're looking to fill at the moment? Dr. Jason Weatherald:   Ideally, I think it would be a noninvasive way to look at the right ventricle that is cheap, reproducible, and gives us the same confidence that invasive hemodynamics do. Although I find echo is indispensable and MRI is very useful, I think at the end of the day, we all go back to the right heart catheterization and we need to find something that can replace that, but give us the same confidence in what we think we're measuring and that it reflects treatment changes and clinical worsening. Dr. Carolyn Lam:               And Kelly, what do you think should be next steps? Dr. Kelly Chin:                    I have to say I really liked this study. I thought it moves us forward in assessment of prognosis for this population of patients in a really big way. It was large and included a large number of measures that were done very carefully. You always want to see replication.                                                 But, what I'd also like to see is the other forms of pulmonary arterial hypertension. You know this focused mainly on the idiopathic PAH patients, so what happens in connective tissue disease, and also what happens late after treatment, because I think we sometimes see a little bit of a different phenotype in patients that we've treated for many years and sometimes hemodynamics have improved, but in different ways than what we see early on with initial therapies. Dr. Carolyn Lam:               You've been listening to Circulation on the Run. Tune in again next week.  

Major advances in understanding and treating breast cancer have been made in the last two decades, yet it remains a significant problem with breast cancer being the most commonly identified cancer and the leading cause of cancer death among women worldwide. For many years breast cancer research has mainly focused on genetically changed cancer cells. However, recently the importance of the stromal compartment surrounding cancer cells in facilitating tumor growth, invasion and metastasis has been widely recognized. Cumulating evidence suggests that in particular carcinoma-associated myofibroblasts play a key role within the tumor stroma and influence many aspects of carcinogenesis. Nevertheless, the cell type of origin as well as the precise mechanisms by which these cells develop has not been conclusively established and remains controversial. The role of human adipose tissue derived stem cells (hASCs) in this context has not been studied so far. hASCs are locally adjacent to epithelial breast cancer cells and might represent early response cells within the tumor stroma. Hence, the aim of this study was to investigate whether carcinoma-associated myofibroblasts may originate from hASCs. The present study revealed that a significant percentage of hASCs differentiate into myofibroblast-like cells expressing alpha smooth muscle actin (α-SMA) and tenascin-C when exposed to conditioned medium from the human epithelial breast cancer cell lines MDMAB231 and MCF7. This process is induced by transforming growth factor beta 1 (TGFβ1) secreted from breast cancer cells. It was shown that conditioned medium from MDMAB231 and MCF7 contains significant amounts of TGFβ1. It could further be demonstrated that the differentiation of hASCs towards myofibroblasts is dependent on TGFβ1 signaling via phosphorylation of Smad2 and Smad3 in hASCs. The induction of myofibroblasts can be abolished using a neutralizing antibody to TGFβ1 as well as by pretreatment of hASCs with SB431542, a selective inhibitor of the TGFβ1 activin receptor-like kinases 4, 5 and 7. Additionally, hASC-derived myofibroblasts exhibit functional properties of carcinoma-associated myofibroblasts such as the increased secretion of the tumor-promoting soluble factors SDF-1α and CCL5. Furthermore hASC-derived myofibroblasts as well as conditioned medium from these cells promote the in vitro invasion of MDAMB231 breast cancer cells. Moreover inhibition of the TGFβ1 signaling pathway in hASCs reduces the potential of these cells to enhance the invasion of breast cancer cells. Overall, the data of the present study suggest that human adipose tissue derived stem cells can differentiate into carcinoma-associated myofibroblast under the influence of TGFβ1 secreted from breast cancer cells in vitro. The differentiation of hASCs towards these tumor-promoting cells can be abolished by targeting the TGFβ1 signaling pathway. Hence, inhibition of the TGFβ1 signaling pathway may prove to be an interesting target for breast cancer therapies. In vivo studies on the cancer microenvironment under special consideration of the interactions between hASCs and cancer cells should be of interest for breast cancer research in the future.