Podcasts about dharam

After entertaining young and old alike on the idiot box for more than a decade. the iconic animated heroes – Bade and Chote will now infiltrate the podcast scene with their brand of nonsensical ‘bakwaas' that is guaranteed to make your day!

Thank you for listening!!  Host,  Nani NRIPelliGola Podcast ⁠⁠⁠⁠⁠https://www.instagram.com/nripelligola/⁠⁠⁠⁠ ⁠https://www.instagram.com/storiesbytwoplusone/ --- Send in a voice message: https://podcasters.spotify.com/pod/show/nri-pelli-gola/message

NCNS Guiding Teacher Myozen Joan Amaral gives a Dharam talk to the Sangha on July 9th 2023

In this inspiring podcast episode, Jess Zarowitz engages in a captivating conversation with Michelle, delving into the transformative power of yoga and its profound impact on her life's calling, or Dharam. Through Michelle's illuminating insights, listeners will discover how the practice of yoga can bring about positive changes in their own lives. Moreover, both women share their valuable experiences of collaborating with other yoga teachers and how working together has created a positive impact on the wider yoga community. Listeners will gain valuable insights into how coming together to uplift one another can create a thriving and supportive collective community within the world of yoga. If you're looking to deepen your yoga practice, connect with like-minded individuals, and make a positive impact within your community, this conversation is a must-listen. So come join us as we explore the transformative power of yoga with Jess Zarowitz and Michelle.

5 minute breathwork exercise.

Dharam Kaushik, MD is a urologic oncologist who does big time cancer surgeries.  He is also a researcher and educator at the University of Texas San Antonio where he runs the urologic oncology fellowship program and leads the kidney cancer research program.  Despite an upbringing in India and early exposure, he only recently picked up yoga as an outlet for wellness in his life.  We explore yoga and mindfulness as strategies to combat burnout and stress at work, but expand the discussion to other forms of physical activity that can improve our surgical well-being.  During the COVID pandemic, Dharam was certified as a yoga instructor and now expands his practice to healthcare workers at UT San Antonio – offering free classes to any employee or student who is interested.  And he doesn't take it easy on them!  He talks and teaches about suffering and struggle in a yoga class as a great metaphor for surgery and life.  I love talking with Dharam and I hope you do too.  If interested in a yoga class or experience at a urology meeting, please find Dharam or I and join us or we can help to set it up.  And stay tuned for some bonus content!  Dharam will take us through a breathwork exercise that you can use anytime to prepare for surgery, destress, or as part of your mindfulness routine.

This week Jens sits down with one of his co-workers to discuss the relationship between faith and business. Jens and Kailey work for a unique company that operates within a unique industry. They break down how their faith shapes and informs what they do on a daily basis, how culture is shaped at a non-faith-based organization, and offer insight into navigating the complexities of work and business as Christians.   Find us on: Email: doxologypodcast@gmail.com Twitter: @doxologypodcast Instagram: @doxologypodcast

Please join author Petr Ostadal and Associate Editor Dharam Kumbhani as they discuss the article "Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock: Results of the ECMO-CS Randomized Clinical Trial." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Peder Myhre: And I'm Dr. Peder Myhre, social media editor from Akershus University Hospital and University of Oslo in Norway. And today Carolyn will have such an interesting feature discussion. We are going to look into the use of ECMO to treat patients with cardiogenic shock, the results of the ECMO-CS randomized clinical trial. Isn't that interesting? Dr. Carolyn Lam: Awesome. Can't wait. But I suppose you're going to tell us about some papers in the issue first. I'm getting my coffee. Dr. Peder Myhre: Yeah, go ahead. Because first we're going to talk about a very interesting paper that relates to diabetes and the progression of coronary artery disease. So as you know, Carolyn, diabetes remains associated with an increased risk of cardiovascular morbidity and mortality. And although the absolute risk difference between patients with and without diabetes have declined over the past 20 years, we still don't know what is the diabetes associated differences in coronary plaque morphology and lipid content. Dr. Carolyn Lam: It's true. That's a very interesting question. And will you tell us more? Dr. Peder Myhre: Yeah. So the investigators in the prospect two study who enrolled patients exclusively from Denmark, Norway in Sweden who presented with biomarker positive MI and assessed both culprit lesions and untreated non-culprit lesions in these patients. And then they stratified the patients by diabetes status and examined with three vessel quantitative coronary angiography and near infrared spectroscopy and intravascular ultrasound imaging after successful percutaneous coronary intervention. Dr. Carolyn Lam: Okay, that's deep investigation. And what did they find? Dr. Peder Myhre: So diabetes was present in about 12% of patients and during a median or 3.7 year follow up, MACE occurred almost twice as free frequently in patients with versus without diabetes. And that was primarily due to an increased risk of MI related to culprit lesion stenosis and non-culprit relation related spontaneous MI. However, baseline prevalence of high-risk plaque characteristics was similar for patients with versus without diabetes, concerning culprit and the non-culprit lesions and in multi-variable models, diabetes was associated with MACE in lesions but not with prevalence of high-risk plaque characteristics. So Carolyn, the authors conclude that diabetes related plaque characteristics that might underlie the increased risk were not identified by multimodal imaging. Dr. Carolyn Lam: Oh, I just love studies like that so elegant with just a really, really intriguing results that make us ask more important questions. Love it. Thank you. Well, the next paper is also about myocardial infarction, but this time looking at the fibrotic remodeling after myocardial infarction because we know that MI induces a repair response that ultimately generates a stable fibrotic scar. And although the scar is important to prevent cardiac rupture, excessive pro-fibrotic response impairs optimal recovery because it promotes a development of non-contractual fibrotic areas. So would it be possible to regulate the expansion of cardiac fibroblast after MI through a paracrine action on the cardiac stromal cells? So the authors led by corresponding author Dr. Hulot from University of Paris performed a bioinformatic secretome analysis of cardiac stromal PW1 positive cells isolated from normal and post MI mouse hearts to identify novel secreted proteins. And they found that first cardiac PW1 positive stromal cells responded to myocardial infarction by secreting factors that promoted the proliferation and activation of resident fibroblasts and one such factor growth differentiation factor three or GDF3 was highly upregulated in the ischemic hearts and promoted a high induction of fibroblast proliferation via interaction with TGF beta receptors and activation of SMAD1/5 and SMAD2/3 signaling cascades. The upregulation of GDF3 was detected in the plasma of mice and humans following MI and high levels of plasma GDF3 in the days following MI predicted adverse outcomes measured six months later including cardiac dilation and limited recovery of contractile function in humans. Dr. Peder Myhre: Oh, that's so interesting. We already know GDF15 were very well, but now we hear about GDF3 in predicting fibrotic remodeling post myocardial infarction. So Carolyn, what are the clinical implications of these findings? Dr. Carolyn Lam: Exactly, Peder, in fact you said it. So the detection of high circulating GDF3 in plasma may serve as a novel biomarker of adverse fibrotic remodeling in heart tissue. That's one. And next the measurement of GDF3 plasma levels in the early post MI phase may allow for the identification of patients within an increased risk of severe myocardial fibrosis and heart failure and therefore could guide specific disease management. Dr. Peder Myhre: Thank you. That was an excellent summary of the paper, Carolyn. And now I'm going to look into a paper that relates to the important issue of arteriosclerosis following heart transplantation because as you know, transplant arteriosclerosis characterized by concentric and diffuse narrowing of vastly lumen is a major complication in long-term survivors of heart transplant patients. And increased lymph flow from donor heart to host lymph nodes has been reported to play a role in transplant arteriosclerosis. But how lymphangiogenesis affects this process is unknown. The authors of this paper, which comes to us from corresponding author Sue from Sejong University, transplanted vascular allografts between various combinations of mice including mice with severe combined immune deficiency and studied the lymphatic vessels within the grafted arteries. Dr. Carolyn Lam: Wow, that is really cool. Studying lymphatics and lymphangiogenesis in atherosclerosis. Interesting. What did they find, and what are the clinical implications? Dr. Peder Myhre: So Carolyn, lymphangiogenesis within allograft vessels began at the anastomotic sites and extended from preexisting lymphatic vessels in the host. Tertiary lymphatic organs were identified in transplanted arteries at the anastomotic site and lymphatic vessels expressing CCL21 were associated with these immune structures. Fibroblasts in the vascular allografts released VEGFC, which stimulated lymphangiogenesis into the grafts and inhibition of VEGFC signaling inhibited lymphangiogenesis, neointima formation and adventitial fibrosis of vascular allografts. And these studies identified VEGFC released from fibroblasts as signal stimulating lymphangiogenesis extending from the host into the vascular allografts. So, Carolyn, the authors conclude that the formation of lymphatic vessels play a key role in the immune response to vascular transplantation and inhibition of lymphangiogenesis may be a novel approach to prevent transplant atherosclerosis. Dr. Carolyn Lam: Wow, that is super interesting. Thanks, Peder. While also in this issue, there's an exchange of letters between Drs. Tanaka and Schulze regarding SGLT2 inhibitor treatment in acute decompensated heart failure. Why do we initiate it early? There's also a really nice On My Mind paper by Dr. Schiattarella on Cardiometabolic HFpEF. Is it the NASH of the heart? Dr. Peder Myhre: Oh, that's interesting. We also have some cardiology news by our own ‪Bridget Kuehn entitled “No Benefit Seen for Nighttime Dosing Over Morning Dosing for Antihypertensive Medications.” And this is a summary of the time trial, which was presented at European Society of Cardiology Congress in 2022. And finally, Carolyn, we have a Research Letter entitled “Stepwise Generation of Human-Induced Pluripotent Stem Cell Derived Cardiac Parasites to Model Coronary Microvascular Dysfunction” by Dr. Joseph Wu from Stanford University School of Medicine. Dr. Carolyn Lam: While cool, Peder. But now I'm so excited to hear about the ECMO-CS randomized trial. Let's go. Dr. Greg Hundley: Welcome listeners to this February 7th feature discussion and we have with us today Dr. Petr Ostadal from Na Homolce Hospital in Prague in the Czech Republic and our own associate editor, Dr. Dharam Kumbhani from UT Southwestern in Dallas, Texas. Welcome, gentlemen. Well, Petr, we'll start with you. Can you describe for us some of the background information that really led you to perform this study, and what was the hypothesis that you wanted to address? Dr. Petr Ostadal: According to the current guidelines from the management for the management of cariogenic shock, it should be considered administration of inotropes and vasopressor for hemodynamic stabilization, or it may be considered administration of inotropes and vasopressors and it should be considered the use of short-term mechanical circulatory support. And the aim of the ECMO-CS trial was to compare early conservative therapy with inotropes and vasopressors and immediate implementation of ECMO in patients with the rapidly deteriorating or severe cardiogenic shock. The hypothesis of the ECMO-CS trial was that immediate implantation of ECMO in patients with cardiogenic shock and critical hemodynamic condition will be associated with improved outcomes. Dr. Greg Hundley: Very nice. Can you describe for us this study population and then also what study design did you use to address your hypothesis? Dr. Petr Ostadal: We try to select patients who can really profit from the early ECMO implantation, and we define two categories of patients. First category where the patients with rapidly deteriorating cardiogenic shock corresponding to current sky stage D or E. This patient should have evidence of left ventricle pump failure as left ventricle ejection fraction below 35% or ejection fraction 35 to 55 in case of severe mitral regurgitation or aortic stenosis. And this patient also should require a repeated both of vasopressors to maintain mean arterial pressure about 50 millimeters of mercury. The second category where the patients with severe cardiogenic shock corresponding to current sky stage D and this patient should have the criterion of a hemodynamic conditions which was cardiac index less than 2.2 or systemic blood pressure below 100 millimeters of mercury in both situation with higher doses of inotropes and vasopressors. And in case of a low systolic blood pressure, also the evidence of left ventricle pump failure based on ejection fractional below 35 or ejection fraction 35 to 55 in case of severe mitral regurgitation of aortic stenosis. The second criteria for the metabolic criteria, that was the evidence of tissue hypoperfusion and this was defined as a higher lactate above three millimeters per litter or low ScvO2 below 50%. And the third criterion was exclusion of hypovolemia, and this was based on central venous pressure or pulmonary artery wedge pressure. So this was the major inclusion criteria in the ECMO trial. The study population was not defined based on theology of cardiogenic shock, but just on severity of cardiogenic shock. Dr. Greg Hundley: Very nice. And so your design, did you have a one-to-one randomization, or how did that work? And then also how many subjects did you include in this important trial? Dr. Petr Ostadal: The patients were randomized in one-to-one ratio to immediate implementation of ECMO or to early conservative therapy. But it is important to point out that in the early conservative therapy downstream use of ECMO was allowed in case of further hemodynamic worsening defined as increase of what lactate by three millimeters per litter. We enrolled 122 patients, 61 were randomized to early ECMO and 61 to early conservative strategy. Five patients were excluded due to absence of informed consent and finally 58 patients were analyzed in the early ECMO or immediate ECMO arm and 59 patients were analyzed in the early conservative arm. Dr. Greg Hundley: Sounds great Petr. And then tell us and describe your study results. Dr. Petr Ostadal: The primary endpoint was composite of death from any cause, resuscitated circulatory RS and implementation of another mechanical circulatory support including ECMO in the early conservative arm at 30 days. And there was no difference in the primary endpoint with P 0.2221 and has a ratio of 0.72 with a 95% confidence in interval 0.46 to 1.12. There was also no difference in the incidence of death from any cause. 50% in the immediate ECMO arm and 28%, 47.5% in the early conservative arm. There was no difference in the incidence of resuscitated circulatory arrest, 10.3 in the immediate ECMO arm and 13.6 in the early conservative arm. Less patient required another mechanical circulatory support in the early ECMO arm through 17.2 in comparison with 42.4% in the early conservative arm and downstream ECMO was used in 39% of patients in the early conservative arm. Dr. Greg Hundley: Very nice. So similar results both immediately and then 30 days later for both arms. And I think that last point that you make is very interesting. 39% of the individuals randomized to the conservative arm went on to receive VA-ECMO. Well, listeners next, we're going to turn to one of our associate editors and Dharam, you have many papers that you see. How do we put the results that Petr has just described really in the context of management of shock and results that have been published previously? Dr. Dharam Kumbhani: Yeah, Greg, thank you. And Petr, thank you for this important paper and again, I'm really honored to be here on behalf of Circulation on the Run. So again, want to congratulate the authors for really an important study. I think in terms of context, what is really interesting is the use of ECMO, particularly VA-ECMO for patients with shock has really skyrocketed. And it is interesting that this expansion has occurred in the absence despite, I guess high quality clinical trials, this trial certainly fills an important void. Although it is a small patient population, it is randomized, it is a largest randomized trial to date on this important population. And so I think most of the studies that have been done so far have been done using observational data sets which have sort of inherent limitations. So I certainly want to congratulate you on trying to study this very challenging population because in sort of that acute setting, it's frequently very hard to get patients randomized. So just broadly in that context, I think at the same time this study does sort of pose some important questions and sort of perhaps leads, just given the limitations of the sample size does sort of leave a few unanswered questions. So one question I have is, Petr, in addition to the 40% crossover rate is obviously important as Greg pointed out. The other thing is it appears that the use of other mechanical support during the conduct of this trial was also close to 40%, about 42%. So pretty much everybody in the conservative arm ended up with some kind of mechanical support. Now, at least in the last few years, a concept that has gained a lot of traction is a concept of a shock team where a number of providers with particular expertise from different disciplines would get together and sort of decide next steps was a shock team sort of part of the decision-making, especially for the conservative arm. Dr. Petr Ostadal: Thank you for this question. The situation is maybe a little bit more simple in the Czech Republic here, the cardiologist are responsible for the acute cardiac care, usually competent and experience not only for the diagnosis and examinations and monitoring of patients in cardiogenic shock, but also experience in insertion and management of the mechanical circulatory support. So here this attending cardiologist competent to manage this patient from different sites from the manage not only the conservative therapy but also the mechanical circulatory support therapy in these patients. So in this respect, this is more simple situation in the Czech Republic. Dr. Dharam Kumbhani: I just had a very quick question about, and I don't know if you want to include this, but Petr, I was curious, were patients with cardiac arrest, I know you mentioned sky shocks in were patients with cardiac arrest on the field or in the hospital included? Dr. Petr Ostadal: Thank you for this excellent question. And in comparison, with other trials comparing the or focusing on patients with cardiogenic shock in the ECMO-CS trials, cardiac arrest survivors were excluded. And the reason was that the brain damage, which is the major cause of death in these patients cannot be influenced by ECMO insertion. And second, in majority of patients after cardiac arrest, if there is a presence of shock, there is frequently combined shock with important peripheral component. And again, it cannot be assumed that this peripheral component can be reversed by ECMO implantation. So in the ECMO-CS trial, the cardiac arrest survivors were excluded from that enrollment. Dr. Greg Hundley: Well, thank you so much Petr. Petr, what do you think is the next study to be performed really in this area of research? Dr. Petr Ostadal: I think that we are happy because several other clinical trials focusing on the mechanical circulatory support in patients with cardiogenic shock underway. And there are other trials focused on ECMO and trials a bit focused on combination of ECMO with balloon pump and trials focused on Impella. So I think in the very close time we will be able to see the results of these current running trials1. Dr. Greg Hundley: And Dharam, do you have anything to add? Dr. Dharam Kumbhani: No, I agree completely with Petr. I think this is a very exciting field. I know there's a lot of interest in doing well conducted clinical trials in this space. And so certainly, I think the future is bright for investigation in this field. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Petr Ostadal from Prague in the Czech Republic and our own associate editor, Dr. Dharam Kumbhani from Dallas, Texas for bringing us this study highlighting that immediate implementation of VA-ECMO in patients with rapidly deteriorating, or severe cardiogenic shock did not improve clinical outcomes compared to an early conservative strategy that permitted downstream use of VA-ECMO in the case when the patient's hemodynamic status worsened. Well, on behalf of Carolyn, and Peder, and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This newest episode is with Sat Dharam Kaur, Kundalini Yoga teacher, naturopath, co-creator of the Compassionate Inquiry therapeutic approach with Dr. Gabor Maté's and a great inspiration in my own life. Throughout this episode Sat Dharam allows us a peek into the world of Kundalini Yoga and her life with it; she shares about her Beyond Addictions program as well as the work with Dr. Gabor Maté's Compassionate inquiry program. This brand new episode guides us through the following points: The benefits Sat Dharam experiences with Kundalini Yoga, what the practice entails, how mantra revels itself to us and how it enables her intuition becomes clear to her allowing her to hear her soul's purpose *The underlying reason people struggle with addiction and how some parts of ourselves that are unexpressed result in many people creating patterns to self-sooth. Sat Dharam's Beyond Addictions program and how it teaches learning to have compassion and acceptance for ourselves in a safe space to build connection to our true selves, change those patterns and process our pain. Sat Dharam's role in how Compassionate Inquiry with Dr. Gabor Mate was created and their collaboration teaching and formulating the method, the components, skills and line of inquiry that comprise the program. Christina and Sat Dharam model Compassionate Inquiry to showcase the approach and how it's practiced. Christina vulnerably shares a situation that's brought stress within her life They work together identifying feelings within the body and what comes up when discussing the inquiry Sat Dharam and Christina get to bottom of when she first felt this way, and the core memory that this feeling stems from They find a parallel within Christina's life to understand the experience of anyone in this situation, how they would cope, grow and how this feeling or experience would shape them Christina and Sat Dharam discuss how anyone in this situation could be supported and what that support would look like They conclude by identifying how Christina would have felt if she were supported within the situation at the time, what she would like to say to that part of herself she still carries with her and what in return that self needs to feel safe moving forward What Sat Dharam has coming up in both her offerings with Beyond Addictions, Compassionate Inquiry and joyfully within her personal life We hope you enjoy this episode! Listen up and leave your feedback below! Learn more about Sat Dharam here. Learn more about Ananda Soul Jewelry: https://anandasoul.com/ Learn more about our host Christina Zipperlen: https://www.sensitivematters.com/about

Satgur Dharti Dharam Hai, ਸਤਿਗੁਰੁ ਧਰਤੀ ਧਰਮ ਹੈ (Sri Guru Granth Sahib Page 302 Sabad 750)

#HinduDialogues: Dharam Rajya-The Hindu State| Q&A | Part 2| Shankar B Khandavalli| #SangamTalks SrijanTalks

"Ready, Set, Go" Missions Conference 2022

Guru Nanak talks describes where to get Dharam from. And how to meet the Lord within. --- Support this podcast: https://anchor.fm/gurmatsaanjh-hindi/support

Shuklambar Dharam Vishnu is considered to be one of the most potent slokas related to Lord Vishnu.

Pravind Jugnauth évoque un appel de Veena Ramgoolam au Parlement : La Voice of Hindu par l'entremise de NavinUnnoop condamne les paroles utilisées par le Premier ministre ;« Sauvegarde le Dharam...Mo ti a souhaiter qui le premier ministre réfléchi et li reprend so mot », avise le dirigeant de la VOH Suite à une question de Kenny Dhunoo, hier au parlement, sur les frais médicaux du Dr Navin Ramgoolam qui était souffrant, Pravind Jugnauth a évoqué un appel de Veena Ramgoolam. Ce qui a provoqué de vives protestations de l'opposition, dans la foulée Shakeel Mohamed, MahendGungapersad et Patrick Assirvadenont été expulsés. La Voice of Hindude son côté, par l'entremise de NavinUnoop condamne avec force les paroles utilisées par le Premier ministre concernant l'épouse du Dr Navin Ramgoolam. Il demande ainsi à Pravind Jugnauth de retirer ses mots pour faire honneur aux femmes et à la communauté mauricienne. « Quel exemple, quel signal est-on en train d'envoyer à nos jeunes ?!Ce n'est pas correct d'utiliser une affaire aussi privée au Parlement !»,dénonce le dirigeant de la Voice of Hindu.

Dhahan Lage Dharam Rai, ਢਾਹਨ ਲਾਗੇ ਧਰਮ ਰਾਇ (Sri Guru Granth Sahib Page 256 Sabad 676)

Is Jug Ka Dharam Parahu Tum Bhai, ਇਸੁ ਜੁਗ ਕਾ ਧਰਮੁ ਪੜਹੁ ਤੁਮ ਭਾਈ (Sri Guru Granth Sahib Page 230 Sabad 611)

Veronica Joseph brings you the news from the Supreme Court, New Delhi, Maharashtra, and the United States. See acast.com/privacy for privacy and opt-out information.

DHARMENDRA AND HEMA MALINI WERE UNABLE TO MEET EACH OTHER FOR ALMOST ONE YEAR .WHY ?

Guru Nanak Ji ne Koi Dharam Nahi Chalaya Episode 46

In this katha by Giani Jiva Singh (Damdami Taksal wale) talks about Kshatriya Dharam as defined by Sri Guru Gobind Singh Ji. Any issues please contact me on kam1825@hotmail.com I would also like to thank my sponsors who have donated towards the podcasts financially. Thank you with your continuing support this podcast can become self sustaining

In Episode#3 of Pitch Cafe, I talk with Dharam Singh, CEO, PgMP, PfMP, PMP, RMP, ACP, PBA, DASM, DASSM, PMI-ATP

Please join author Ole Fröbert and Associate Editor Dharam Kumbhani as they discuss the article "Influenza Vaccination After Myocardial Infarction: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center in Duke National University of Singapore. Dr. Greg Hundley: I'm Dr. Greg Hundley, associate editor, director of the Poly Heart Center at VCU health in Richmond, Virginia. Well, listeners, this week we've got a really hot feature topic pertaining to flu vaccines, which are coming in the US, North America, South America, coming up soon, and their relationship to myocardial infarction. But before we get to that feature discussion, let's grab a cup of coffee and jump in to some of the other articles in this issue. Oh, wait a minute. Our first article, we've got a co-author here. Carolyn, something about the VICTORIA trial, which you were a part of. Can you tell us a little bit about this? Dr. Carolyn Lam: I would love to, and first of all, I'm doing this on behalf of a big team, and I want to really, really call up first Dr. Paul Armstrong who's the senior author from University of Alberta. But let me tell you first about the VICTORIA study. VICTORIA evaluated vericiguat, a soluble guanylate cyclase stimulator, compared to placebo, in patients with heart failure with reduced ejection fraction with a recent worsening heart failure event and the primary result was actually a significant reduction in the primary composite outcome of cardiovascular death or heart failure hospitalization with vericiguat compared to placebo. Dr. Carolyn Lam: Now, interestingly though, in VICTORIA, we found that anemia occurred more often in patients treated with vericiguat at a rate of about 7.6% compared to placebo, which was 5.7%. Now, although earlier studies of another soluble guanylate cyclase stimulator like riociguat was found to be associated with anemia. The etiology really remains unknown. In the current paper, we explored the relationship between markers of anemia and vericiguat versus placebo in VICTORIA. We further explored the changes in hemoglobin and hematocrit over the course of the trial and their relationships with the primary composite outcome. Dr. Greg Hundley: Carolyn, this is such an important new study heart failure therapy for those with reduced ejection fraction, and again, an important topic related to anemia. What did they find? Dr. Carolyn Lam: Thanks, Greg. First, approximately a third of patients in VICTORIA had anemia at randomization, and this is using the standard sex-based definitions. With a lower hemoglobin indeed predicting a higher risk for cardiovascular death, heart failure hospitalization, all-cause mortality. As I had already mentioned, we found more anemia with vericiguat than with placebo. The interesting thing though is after 16 weeks, no further decline in hemoglobin occurred over the remaining and over 96 weeks of follow up, and the ratio of hemoglobin to hematocrit remained constant. Now, overall, the adverse event of anemia occurred in 7.1% of the patients. Dr. Carolyn Lam: Importantly, the lower hemoglobin was not related to the beneficial effect of vericiguat over placebo on the primary outcome. Now, I know all of that may be more descriptive and reassuring than really understanding the mechanism by which it occurred. Further mechanistic studies are certainly warranted to better understand the basis of the anemia development, and it's of principle importance because as you said, vericiguat I think it's going to be an important new medication that we can consider in high-risk patients with recent worsening heart failure with reduced ejection fraction. Dr. Greg Hundley: Thanks so much, Carolyn, especially the perspective of being an author on this particular study. Well, Carolyn, my next study is going to come to us from Dr. Zhao Wang from University of Texas Southwestern Medical Center, and it's really about the integrated stress response, and that's an evolutionary conserved process to cope with intracellular and extracellular disturbances. Myocardial infarction is a leading cause of death worldwide. Coronary artery perfusion is the most effective means to mitigate cardiac damage resulting from myocardial infarction. However, that can cause, as we know, additional reperfusion injury. This study aim to investigate the role of the integrated stress response in myocardial ischemia reperfusion injury. Dr. Carolyn Lam: Oh, very interesting. What were the results? Dr. Greg Hundley: Right, Carolyn. The authors found that the integrated stress response is activated by ischemia reperfusion injury in the heart, and the perk branch of the integrated stress response protects the heart from ischemia reperfusion injury through inhibition of protein synthesis. Also, Carolyn, mitochondrial complex proteins are selectively suppressed and oxidative stress is reduced by the integrated stress response. Carolyn, the takeaway is that this integrated stress response is cardioprotective against cardiac ischemia reperfusion injury. Perhaps pharmacological stimulation of the integrated stress response at reperfusion, well, that may reduce heart damage and improve cardiac outcomes after ischemia reperfusion injury. Dr. Carolyn Lam: Cool. Thanks, Greg. Well, I've got one more paper, and this deals with coronary microcircuitry dysfunction and acute rejection after heart transplantation. Co-corresponding authors, Doctors Lee and Choi from Heart Vascular Stroke Institute in Samsung Medical Center sought to evaluate the prognostic implications of coronary microcircuitry dysfunction assessed by the index of microcircuitry resistance or IMR for the risk of acute cellular rejection after heart transplantation. They did this by prospectively enrolling 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiological assessment one month after transplantation.   Dr. Greg Hundley: Very interesting, Carolyn. What did they find here? Dr. Carolyn Lam: IMR measured early after heart transplantation was significantly associated with the risk of acute cellular rejection, and an IMR above or at 15 was highly predictive for the recurrence of acute cellular rejection during two years of follow up following heart transplantation. Adding IMR to the prediction model with clinical variables significantly increase discriminant and reclassification ability for the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, the implications are that early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation, and this is discussed in an editorial by Doctors Fearon and Valentine from Stanford University. Dr. Greg Hundley: Very nice, Carolyn. Dr. Carolyn Lam: Great. Greg, before we go to the exciting feature discussion, let's round it up by just a quick tour of what else there is in today's issue. There is an exchange of letters between Doctors Pappone Leor on atrial fibrillation as a cardiomyopathy, global rounds on United Kingdom by Dr. Cowie, an ECG challenge by Dr. Tsai on grouped beating following acute inferior myocardial infarction, and a research letter by Dr. Salem on electrocardiographic manifestations of immune checkpoint inhibitor myocarditis. Dr. Greg Hundley: Great, Carolyn. Well, I can't wait to get to this next feature discussion and learn a little bit more about the relationship between flu vaccines and future myocardial infarction. Dr. Carolyn Lam: Today's feature discussion was a really hot topic at the ESC 2021, and in fact, a simultaneous publication. It is about influenza vaccination after myocardial infarction, a very important topic and a very novel paper. We are so pleased to have the first and corresponding author, Dr. Ole Fröbert from Orebro University in Sweden to discuss this paper, as well as our associate editor, Dr. Dharam Kumbhani, from UT Southwestern. Welcome, gentlemen. Only if I could start with asking you to describe the rationale for why you did this study, and then perhaps quickly summarize the results. Dr. Ole Fröbert: Yeah, thank you so much, Carolyn. The background of the study was that during influenza epidemics, more people die from cardiovascular causes, and out in the literature, there are numerous observational studies suggesting a protective effect from influenza vaccination on cardiovascular events. There are also three smaller single-center randomized trials supporting these registered findings. Currently influenza vaccination carries a Class I, Level of Evidence B recommendation in both American and European secondary prevention guidelines, but uptake is low and vaccination timing is unclarified. Our aim was to determine whether influenza vaccination improves clinical outcomes in patients with a recent myocardial infarction or with high risk corona artery disease. Dr. Ole Fröbert: The study was international, multi-centers investigator initiated, double-blind randomized control trial, and we enrolled patients at 30 centers across eight countries in both the Northern and the Southern Hemisphere, Sweden, Denmark, Norway, Latvia, Scotland, Czech Republic, Bangladesh and Australia. We enrolled patients between October 2016 and March 2020. We had quite broad inclusion criteria. We included hospitalized patients with STEMI or non-STEMI, or high-risk stable patients over 75 years of age undergoing an angio or PCI. We excluded patients already vaccinated or intending to be vaccinated during the current season. We also included, of course, patients if they had allergy to X or influenza vaccine, if they had infection or if they were immunosuppressed or previously randomized in the trial. Dr. Ole Fröbert: Over these four years of inclusion, we enrolled a total of 2,571 participants. The primary outcome was a composite of all-cause death, MI and stent thrombosis. This outcome occurred in 67 participants assigned influenza vaccine and 91 assigned placebo corresponding to a reduction of the primary endpoint of 28% with a P value of 0.04. Also, rates of all-cause death and of cardiovascular death were reduced and both with a hazard ratio of 0.59 corresponding to a reduction of 41% in all-cause death and cardiovascular death. Based on these results, we think that this trial and what we know from previous smaller trials should be sufficient to establish influenza vaccination as a new standard of care as part of in-hospital treatment after an MI. Dr. Carolyn Lam: Heartfelt congratulations, Ole. What an elegant intervention in a very frankly challenging situation that the trial obviously carried on through COVID as well, multinational. May I just double check? Was it investigator-led? Because- Dr. Ole Fröbert: Yes, this was- Dr. Carolyn Lam: That's amazing. Dr. Ole Fröbert: ... an idea that just popped up, and then yeah, we did it, but it was seven years of work. Dr. Carolyn Lam: Wow. Hard work as I can just imagine. First, heartfelt congratulations. Very impactful results. Dharam, could I invite you to put those results in context and why we single this out? Dr. Dharam Kumbhani: Yeah. No, thank you, Carolyn. Ole, I want to amplify or recapitulate the amazement and wonder that Carolyn just articulated. I think this is a huge endeavor. It's a very important topic. It's "a fairly simple intervention." It's vaccination, and you've just really shown that even in the acute setting, that A, this is as feasible, B, it is safe, and three, it is effective. I think it's potentially ... Given the magnitude of influenza in the world, I think this has tremendous public health ramifications. I really want to congratulate you and your investigators for pursuing this important question and then just executing this, I'm sure despite multiple challenges over a long period of time. Dr. Ole Fröbert: Thank you very much. Dr. Dharam Kumbhani: Yeah, no. I guess you already alluded to the fact that this may influence guidelines. As you mentioned, it's a 1B. Maybe get your thoughts, I suppose this may move the needle towards becoming perhaps a little stronger on the recommendation front, both in the US and the European guidelines? Dr. Ole Fröbert: Yeah. I think what has been the challenge until now is that many places, of course, you commend patients to take a flu jab when treatment is over in the hospital. But then the responsibility is diffused. Who should take care of that? Is that up to the patient or the primary care physician? Who is in charge? One important finding of this study is, as you said, it's safe. There were no differences, adverse events between the two groups. It's safe and it could be given early. I think a take-home factor from the study is that it should be given at the hospital and it's a responsibility of the cardiologist. Dr. Dharam Kumbhani: Yeah, I really like that. Actually, I'm sure this would resonate across the board in the cardiology community. We've taken ownership for starting from statin and now SGLT-2 inhibitors, which kind of ... All of these medications have come from non-cardiology realms, so to say. But now we prescribe those medications. We know they have clear cardiovascular benefits. I suppose you could make a case to say we, the cardiology community, has to adopt this. The implementation gap that exists for a lot of these therapies, that also comes to us and for us to move that forward. It's thought provoking. I certainly felt very strongly after your study. I don't know how you feel about that. We should really be the ones driving this and help with more widespread immunization in these patients. Dr. Ole Fröbert: I think because not just this study, but also the previous studies and what we know from observational findings is that this is safe and it works. What we also saw in our study, and it has been indicated in previous meta analysis, is that the maximum effect is seen in the acute setting. It's the acute coronary syndrome patients, the patients we had in our study, that benefit the most. That's also a case for actually doing this in the hospital and not postponing it. Dr. Carolyn Lam: Wow. That's amazing. Ole, I do have one question. Just for clarification. You were careful to say that you did this during influenza seasons, right? Coming from my part of the world in Singapore where we don't really have influenza seasons, don't have any seasons, frankly, what would you think? What would you advise? Dr. Ole Fröbert: There is influenza seasons in all parts of the world, I'm sorry. Dr. Carolyn Lam: True. Dr. Ole Fröbert: For example, we had Bangladesh on board in our study. It's in the Northern Hemisphere, but influenza-wise, it's in the Southern, and their season is between May and September. But it's not as clearly defined as the Northern Hemisphere season. It's almost always in two waves during that season. One practical challenge with influenza vaccine is that it's produced for the seasons. It's difficult to say, "Yeah, we can just do it all year round," and also we didn't test that. I, of course, feel we should give it all year round, but it's not available, the vaccine. Perhaps it should be tested, but it is probably difficult to find funding for such a study. Dr. Carolyn Lam: Very fair, and thanks for the correction. It's true though. Singapore's on the Equator, so we don't have maybe weather seasons. But yeah, we do get vaccinated for both North and South. It's quite fascinating. But nonetheless, could I now switch topics a little bit and just over the next couple of minutes just ask you, could you please perhaps share with the audience what it was like to work with Circulation, to do this simultaneous publication? You see, our associate editor, Dharam Kumbhani, really leads this effort to get simultaneous a fast-track publication from major conferences, and it means a lot to us that investigators like you chose us. Could you share a bit? Dr. Ole Fröbert: Yeah, thank you very much. Overall, it was a pleasure. Of course, we were ... With every study of this size, you are under stress, you get the results late, and there's a conference coming up, and you would like your paper to come out at the same time across to maximize impact and attention. What I really like with working with Circulation was turnaround time was ultra fast, really extremely fast. Of course, we had a lot of questions to our study, but these were ... Some of them of course were quite difficult, but they were fair. In a way, they were also helpful in a way that made it easier to address the questions in a more, you could say, collaborative way. It was very smooth. No hiccups. Dr. Carolyn Lam: Thank you. Dharam, any final responses to that? Dr. Dharam Kumbhani: No, thank you, Carolyn. Yeah. Well, Ole, it was really a pleasure to work with you on this. I think we all recognize that this was an important study and wanted to make sure that we were able to accomplish the goal of simultaneous publication. Thank you for working with us on that. I just want to put a pitch in, I think this, for Joe, Dr. Hill and the rest of the editorial team, having a robust simultaneous publication program has been very, very important. We are very committed to working with investigators and authors on this. We are really blessed with our team on the backside that works seamlessly with us nights, weekends, just to get these things done. I just want to end with that to say this is very important for us, and we look forward to the opportunity to work with Ole and others on future papers as well.   Dr. Carolyn Lam: I love that. Thank you both for being on this podcast today. Today I want to especially call out David Rivera, a wonderful managing editor who really, really is part of leading this entire group that supports us, but also even this very podcast. You've been listening to Circulation on the Run. Thank you, from both Greg and I, for joining us today, and don't forget to tune in again next week. Thank you. Dr. Greg Hundley: This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

This is a powerful Krishna Mantra. One should recite it 33 times during Adhika Masa or Purushottama month. Mala masa is another name for this month, which means dirty or useless month. In India, pious Hindus perform rigorous austerities (vratas) during this month. It is considered a dirty month because Poojas and Yajnas supposedly don't give any results during this time. But others feel that it got this name because spiritual activities performed during this month can destroy the dirt we accumulate due to our sins and ignorance. According to the Puranas, this is Lord Krishna's favorite month. Supposedly, he created it and also gave it his own name. It is called Adhika (extra) Masa as he placed all his powers, mercy, and blessings in this month, and also because devotees get more results from their spiritual activities in this month. In Adhika Masa, it is mandatory to do Daanam or donations of items like thambula, fruits, deepa, gajavasthram, food, clothes, rava laddoos, or anything else, in the count of 33. If it is not possible, chanting this Krishna mantra daily 33 times will suffice. If you would like to find out more about your chart or have a question about astrology you would love the answer to, please do connect with us at www.astroved.com Follow AstroVed on IG, Twitter, and FB @AstroVed

#SantAttarSinghji #Sakhi ਧਰਮ ਦੀ ਕਿਰਤ ਸੰਤ ਜੀ ਮਹਾਰਾਜ ਫ਼ੁਰਮਾਉਂਦੇ ਕਿ ਭਾਈ! ਧਰਮ ਦੀ ਕਿਰਤ ਦੇ ਪ੍ਰਸ਼ਾਦੇ ਨਾਲ ਭਜਨ ਵਿੱਚ ਬਿਰਤੀ ਚੰਗੀ ਟਿਕਦੀ ਹੈ। ਇੱਕ ਵਾਰੀ ਧਮਿਆਲ ਪਿੰਡ, ਆਪ ਅਛੋਪ ਹੀ ਬਾਹਰ ਠਹਿਰ ਗਏ ਤੇ ਸੇਵਕਾਂ ਨੂੰ ਮਜ਼ਦੂਰੀ ਕਰਨ ਭੇਜਿਆ। ਸੇਵਕਾਂ ਨੇ ਮਜ਼ਦੂਰਾਂ ਨਾਲੋਂ ਦੂਣਾ ਕੰਮ ਕਰਕੇ ਅੱਧੇ ਦਿਨ ਵਿੱਚ ਹੀ ਸਾਰਾ ਕੰਮ ਪੂਰਾ ਕਰ ਦਿੱਤਾ। ਸ਼ਾਹੂਕਾਰ ਨੇ ਦੁਪਹਿਰ ਨੂੰ ਉਨ੍ਹਾਂ ਦਾ ਕੰਮ ਦੇਖ ਕੇ ਕਿਹਾ, "ਤੁਸੀਂ ਸਾਰੇ ਦਿਨ ਦਾ ਕੰਮ ਅੱਧੇ ਦਿਨ ਵਿੱਚ ਕਰ ਦਿੱਤਾ ਹੈ, ਇਸ ਲਈ ਤੁਸੀਂ ਪੂਰੇ ਦਿਨ ਦੀ ਮਜ਼ਦੂਰੀ ਲਵੋ ਅਤੇ ਜਾਓ। ਪਰ ਸੇਵਕਾਂ ਨੇ ਕਿਹਾ, "ਅਸੀਂ ਸਾਰਾ ਦਿਨ ਮਜ਼ਦੂਰੀ ਕਰਕੇ ਦੂਸਰੇ ਮਜ਼ਦੂਰਾਂ ਜਿੰਨੀ ਹੀ ਦਿਹਾੜੀ ਲੈ ਕੇ ਸ਼ਾਮ ਨੂੰ ਜਾਵਾਂਗੇ"। ਇਸ ਦਾ ਸ਼ਾਹੂਕਾਰ ਦੇ ਮਨ 'ਤੇ ਐਨਾ ਡੂੰਘਾ ਅਸਰ ਹੋਇਆ ਕਿ ਉਸ ਨੇ ਮਹਿਸੂਸ ਕੀਤਾ ਕਿ ਇਹ ਕੋਈ ਮਜ਼ਦੂਰ ਨਹੀਂ, ਬਲਕਿ ਨਾਮ-ਬਾਣੀ ਦੇ ਰਸੀਏ ਹਨ, ਜੋ ਮਜ਼ਦੂਰ ਦੇ ਭੇਸ ਵਿੱਚ ਦਸਾਂ ਨਹੁੰਆਂ ਦੀ ਕਿਰਤ ਕਰ ਕੇ ਪ੍ਰਸ਼ਾਦਾ ਛਕਦੇ ਹਨ। ਇਨ੍ਹਾਂ ਮਜ਼ਦੂਰੀ ਦੇ ਪੈਸਿਆਂ ਦੀ ਰਸਦ ਦਾ ਪ੍ਰਸ਼ਾਦਾ ਛਕ ਕੇ ਸੰਤ ਜੀ ਬੜੇ ਪ੍ਰਸੰਨ ਹੋਏ ਤੇ ਅਗਲੇ ਦਿਨ ਆਪ ਵੀ ਸੇਵਕਾਂ ਨਾਲ ਮਜ਼ਦੂਰ ਬਣ ਕੇ ਮਜ਼ਦੂਰੀ ਕਰਨ ਗਏ। ਮਕਾਨ-ਮਾਲਕ, ਸੰਤ ਜੀ ਮਹਾਰਾਜ ਦੇ ਦਰਸ਼ਨ ਕਰਦਿਆਂ ਹੀ ਚਰਨੀਂ ਢਹਿ ਪਿਆ ਅਤੇ ਕਿਹਾ, "ਸੱਚੇ ਪਾਤਸ਼ਾਹ! ਆਪ ਮਜ਼ਦੂਰ ਨਹੀਂ ਹੋ। ਮੇਰੇ ਗਰੀਬ 'ਤੇ ਮਿਹਰ ਕਰੋ। ਦਾਸ ਸੇਵਾ ਲਈ ਹਾਜ਼ਰ ਹੈ।" ਪਿੰਡ ਦੀ ਹੋਰ ਸੰਗਤ ਨੇ ਵੀ ਇਹੋ ਬੇਨਤੀ ਕੀਤੀ। ਸੰਤ ਜੀ ਨੇ ਬੇਨਤੀ ਪ੍ਰਵਾਨ ਕਰ ਲਈ ਅਤੇ ਕਿਹਾ, "ਚੰਗਾ! ਸਾਨੂੰ ਦਸਾਂ ਨਹੁੰਆਂ ਦੀ ਕਿਰਤ ਕਰਨ ਵਾਲੇ ਘਰਾਂ ਤੋਂ ਪ੍ਰਸ਼ਾਦਾ ਪਹੁੰਚਾ ਦਿਆ ਕਰੋ।" ਸੰਗਤਾਂ ਨੇ ਕਿਹਾ, "ਸਤਿਬਚਨ।" --- Send in a voice message: https://anchor.fm/sant-attar-singh-ji/message

this episode tells the life story of evergreen super star Dev Anand till he got his first movie as written by him in his autobiography ROMANCING WITH LIFE.

T.I.A. (Ep 23). Dharam Singh, founder and CEO of vCare Project Management, and a Program and Portfolio Management trainer and mentor, chats about paths to project, program or portfolio management as a career, essential skills for these roles, and how to overcome major challenges within projects. Dharam also talks about working as a Yoga instructor, using Scaled Agile Framework (SAFe) to deliver projects, his association with a number of PMI Chapters around the world, mentoring programs, and his journey in management roles within Australia and the USA. YouTube: https://www.youtube.com/watch?v=KIyrMgzbfYQ Dharam Singh Website (vCare PM): https://vcareprojectmanagement.com/; YouTube (vCare PM): https://www.youtube.com/channel/UCWg9sBRmPCcpVy2KY5AtjQQ/featured Website (Ask Dharam): https://dharamsingh.co/YouTube; (Ask Dharam): https://www.youtube.com/channel/UCD1Y44xk6N14PsIJTOYEr3Q LinkedIn: https://www.linkedin.com/in/dharamsingh/ Sponsored by The Lewis Institute: Website - https://lewisinstituteinc.com/; Project Leader Courses (60% discount) - https://lewisinstitute.kartra.com/page/Wif255 Business Agility Institute: Emergence Journal - https://businessagility.institute/emergence; promo code "analyst" (for 10% discount on annual subscription)

Kabir Sahib: this story details about how Kabir and Dharam Das met and Dharam Das enlightenment. --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app Support this podcast: https://anchor.fm/milanshree/support

Actor #SaiDharamTej​ in this conversation with Baradwaj Rangan shares his struggles, success and failures in his career. He talks about his upcoming theatrical release #SoloBrathukeSoBetter​ which was supposed to be released on OTT. He talks about what is stardom to him, about his passion and love for acting.

Dharmendra was getting enough publicity being very close to Meena Kumari .

Meena Kumari Supported Dharmendra initially to establish his career in the industry .

Through the kindness of a fellow Gurmat Sangeet premi, the author is introduced to the fabulous kirtan of Bhai Sahib Dharam Singh Zakhmi and his Jatha

Life me har baar aisa hota hai ki sab kuch ho,ya kuch na ho, sawal ek he aata hai ki अब क्या ? Sab kuch to paa liya ,अब क्या ? fir kuch nai hai अब क्या?suniye yea poora episode, iska jawab mil jayega❤

The final podcast in a series of lectures covering the entire explanation of Jap ji Sahib by Guru Nanak Dev Ji. Taught at weekly classes at Slough, UK. This talk covers: - Maning of Salok (Shaloka) - Creation of life through Breath, Father and Mother - All our actions have consequences, some of which we may never be aware of. - Naam (awareness of Oneness) is the destroyer of duality. The words in this verse are: pavan guroo paanee pitaa maataa Dharat mahat. divas raat du-ay daa-ee daa-i-aa khaylai sagal jagat. chang-aa-ee-aa buri-aa-ee-aa vaachai Dharam hadoor. karmee aapo aapnee kay nayrhai kay door. jinee naam Dhi-aa-i-aa ga-ay maskat ghaal. naanak tay mukh ujlay kaytee chhutee naal. ||1||

The next podcast in a series of lectures covering the entire explanation of Jap ji Sahib by Guru Nanak Dev Ji. Taught at weekly classes at Slough, UK. This talk covers: - Talking meditation - Describing God as a meditation - Worshiping demi-gods - There is no end to praise The words in this verse are: amul gun amul vaapaar. amul vaapaaree-ay amul bhandaar. amul aavahi amul lai jaahi. amul bhaa-ay amulaa samaahi. amul Dharam amul deebaan. amul tul amul parvaan. amul bakhsees amul neesaan. amul karam amul furmaan. amulo amul aakhi-aa na jaa-ay. aakh aakh rahay liv laa-ay. aakhahi vayd paath puraan. aakhahi parhay karahi vakhi-aan. aakhahi barmay aakhahi ind. aakhahi gopee tai govind. aakhahi eesar aakhahi siDh. aakhahi kaytay keetay buDh. aakhahi daanav aakhahi dayv. aakhahi sur nar mun jan sayv. kaytay aakhahi aakhan paahi. kaytay kahi kahi uth uth jaahi. aytay keetay hor karayhi. taa aakh na sakahi kay-ee kay-ay. jayvad bhaavai tayvad ho-ay. naanak jaanai saachaa so-ay. jay ko aakhai boluvigaarh. taa likee-ai sir gaavaaraa gaavaar. ||26||

The next podcast in a series of lectures covering the entire explanation of Jap ji Sahib by Guru Nanak Dev Ji. Taught at weekly classes at Slough, UK. This talk covers: - Staying the spiritual path - Honour and glory - Grace and dignity The words in this verse are: mannai maarag thaak na paa-ay. mannai pat si-o pargat jaa-ay. mannai mag na chalai panth. mannai Dharam saytee san-banDh. aisaa naam niranjan ho-ay. jay ko man jaanai man ko-ay. ||14||

The next podcast in a series of lectures covering the entire explanation of Jap ji Sahib by Guru Nanak Dev Ji. Taught at weekly classes at Slough, UK. This talk covers: - 5 vices - Kaam - Desires - Krodh - Anger - Lobh - Greed - Moh - Attachment - Ahunkar - Self importance / identification - 5 virtues - Sat - Charity - Santokh - Contentment - Daya - Compassion - Dharma - Divine living - Sach - Truthfulness The words in this verse are: amul gun amul vaapaar. amul vaapaaree-ay amul bhandaar. amul aavahi amul lai jaahi. amul bhaa-ay amulaa samaahi. amul Dharam amul deebaan. amul tul amul parvaan. amul bakhsees amul neesaan. amul karam amul furmaan. amulo amul aakhi-aa na jaa-ay. aakh aakh rahay liv laa-ay. aakhahi vayd paath puraan. aakhahi parhay karahi vakhi-aan. aakhahi barmay aakhahi ind. aakhahi gopee tai govind. aakhahi eesar aakhahi siDh. aakhahi kaytay keetay buDh. aakhahi daanav aakhahi dayv. aakhahi sur nar mun jan sayv. kaytay aakhahi aakhan paahi. kaytay kahi kahi uth uth jaahi. aytay keetay hor karayhi. taa aakh na sakahi kay-ee kay-ay. jayvad bhaavai tayvad ho-ay. naanak jaanai saachaa so-ay. jay ko aakhai boluvigaarh. taa likee-ai sir gaavaaraa gaavaar. ||26||

The next podcast in a series of lectures covering the entire explanation of Jap ji Sahib by Guru Nanak Dev Ji. Taught at weekly classes at Slough, UK. This talk covers: - The joy of speaking about the divine - Describing meditation - The fools think they know God The words in this verse are: amul gun amul vaapaar. amul vaapaaree-ay amul bhandaar. amul aavahi amul lai jaahi. amul bhaa-ay amulaa samaahi. amul Dharam amul deebaan. amul tul amul parvaan. amul bakhsees amul neesaan. amul karam amul furmaan. amulo amul aakhi-aa na jaa-ay. aakh aakh rahay liv laa-ay. aakhahi vayd paath puraan. aakhahi parhay karahi vakhi-aan. aakhahi barmay aakhahi ind. aakhahi gopee tai govind. aakhahi eesar aakhahi siDh. aakhahi kaytay keetay buDh. aakhahi daanav aakhahi dayv. aakhahi sur nar mun jan sayv. kaytay aakhahi aakhan paahi. kaytay kahi kahi uth uth jaahi. aytay keetay hor karayhi. taa aakh na sakahi kay-ee kay-ay. jayvad bhaavai tayvad ho-ay. naanak jaanai saachaa so-ay. jay ko aakhai boluvigaarh. taa likee-ai sir gaavaaraa gaavaar. ||26||

The next podcast in a series of lectures covering the entire explanation of Jap ji Sahib by Guru Nanak Dev Ji. Taught at weekly classes at Slough, UK. This talk covers: - What is the door and house of God? - See all of creation as a musical show - All of nature sings to God - Creation is the song of life The words in this verse are: so dar kayhaa so ghar kayhaa jit bahi sarab samaalay. vaajay naad anayk asankhaa kaytay vaavanhaaray. kaytay raag paree si-o kahee-an kaytay gaavanhaaray. gaavahi tuhno pa-un paanee baisantar gaavai raajaa Dharam du-aaray. gaavahi chit gupat likh jaaneh likh likh Dharam veechaaray. gaavahi eesar barmaa dayvee sohan sadaa savaaray. gaavahi ind idaasan baithay dayviti-aa dar naalay. gaavahi siDh samaaDhee andar gaavan saaDh vichaaray. gaavan jatee satee santokhee gaavahi veer karaaray. gaavan pandit parhan rakheesar jug jug vaydaa naalay. gaavahi mohnee-aa man mohan surgaa machh pa-i-aalay. gaavan ratan upaa-ay tayray athsath tirath naalay. gaavahi joDh mahaabal sooraa gaavahi khaanee chaaray. gaavahi khand mandal varbhandaa kar kar rakhay Dhaaray. say-ee tuDhuno gaavahi jo tuDh bhaavan ratay tayray bhagat rasaalay. hor kaytay gaavan say mai chit na aavan naanak ki-aa veechaaray. so-ee so-ee sadaa sach saahib saachaa saachee naa-ee. hai bhee hosee jaa-ay na jaasee rachnaa jin rachaa-ee. rangee rangee bhaatee kar kar jinsee maa-i-aa jin upaa-ee. kar kar vaykhai keetaa aapnaa jiv tis dee vadi-aa-ee. jo tis bhaavai so-ee karsee hukam na karnaa jaa-ee. so paatisaahu saahaa paatisaahib naanak rahan rajaa-ee. ||27||

The next podcast in a series of lectures covering the entire explanation of Jap ji Sahib by Guru Nanak Dev Ji. Taught at weekly classes at Slough, UK. This talk covers: - Siddhis - Eighteen spiritual powers of the Siddhas - Mythical and heavenly being sing divine praises The words in this verse are: so dar kayhaa so ghar kayhaa jit bahi sarab samaalay. vaajay naad anayk asankhaa kaytay vaavanhaaray. kaytay raag paree si-o kahee-an kaytay gaavanhaaray. gaavahi tuhno pa-un paanee baisantar gaavai raajaa Dharam du-aaray. gaavahi chit gupat likh jaaneh likh likh Dharam veechaaray. gaavahi eesar barmaa dayvee sohan sadaa savaaray. gaavahi ind idaasan baithay dayviti-aa dar naalay. gaavahi siDh samaaDhee andar gaavan saaDh vichaaray. gaavan jatee satee santokhee gaavahi veer karaaray. gaavan pandit parhan rakheesar jug jug vaydaa naalay. gaavahi mohnee-aa man mohan surgaa machh pa-i-aalay. gaavan ratan upaa-ay tayray athsath tirath naalay. gaavahi joDh mahaabal sooraa gaavahi khaanee chaaray. gaavahi khand mandal varbhandaa kar kar rakhay Dhaaray. say-ee tuDhuno gaavahi jo tuDh bhaavan ratay tayray bhagat rasaalay. hor kaytay gaavan say mai chit na aavan naanak ki-aa veechaaray. so-ee so-ee sadaa sach saahib saachaa saachee naa-ee. hai bhee hosee jaa-ay na jaasee rachnaa jin rachaa-ee. rangee rangee bhaatee kar kar jinsee maa-i-aa jin upaa-ee. kar kar vaykhai keetaa aapnaa jiv tis dee vadi-aa-ee. jo tis bhaavai so-ee karsee hukam na karnaa jaa-ee. so paatisaahu saahaa paatisaahib naanak rahan rajaa-ee. ||27||

The next podcast in a series of lectures covering the entire explanation of Jap ji Sahib by Guru Nanak Dev Ji. Taught at weekly classes at Slough, UK. This talk covers: - 5 Khands of spiritual development - Dharam Khand - Purpose of mankind on Earth The words in this verse are: raatee rutee thitee vaar. pavan paanee agnee paataal. tis vich Dhartee thaap rakhee Dharam saal. tis vich jee-a jugat kay rang. tin kay naam anayk anant. karmee karmee ho-ay veechaar. sachaa aap sachaa darbaar. tithai sohan panch parvaan. nadree karam pavai neesaan. kach pakaa-ee othai paa-ay. naanak ga-i-aa jaapai jaa-ay. ||34||

The next podcast in a series of lectures covering the entire explanation of Jap ji Sahib by Guru Nanak Dev Ji. Taught at weekly classes at Slough, UK. This talk covers: - Giaan Khand - State of Awakening - Expression of euphoria and wonderment - Story of Dhru Bhagat The words in this verse are: Dharam khand kaa ayho Dharam. gi-aan khand kaa aakhhu karam. kaytay pavan paanee vaisantar kaytay kaan mahays. kaytay barmay ghaarhat gharhee-ahi roop rang kay vays. kaytee-aa karam bhoomee mayr kaytay kaytay Dhoo updays. kaytay ind chand soor kaytay kaytay mandal days. kaytay siDh buDh naath kaytay kaytay dayvee vays. kaytay dayv daanav mun kaytay kaytay ratan samund. kaytee-aa khaanee kaytee-aa banee kaytay paat narind. kaytee-aa surtee sayvak kaytay naanak ant na ant. ||35||

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 discussion revolves around important hemodynamic and echo data from the reprise three trial, comparing the lotus and core valve transcatheter aortic valves in patients with high surgical risk. Can't wait? Well it's coming right up after these summaries.                                                 The first original paper this week provide experimental data showing that the endothelium controls cardiomyocyte metabolism and function via notch signaling. Corresponding author, Dr. Fischer, from German Cancer Research Center in Heidelberg, Germany, and colleagues, studied fatty acid transport in cultured endothelial cells and transgenic mice with endothelial specific notch inhibition, or wild type mice treated with neutralizing antibodies against the Notch ligand. They showed that notch signaling in the endothelium controlled blood vessel formation and fatty acid transport in the adult mouse heart. Inhibition of Notch signaling in the vasculature led to expansion of the cardiac vasculature and impairment of fatty acid transport to cardiomyocytes. This resulted in metabolic reprogramming and heart failure.                                                 Together, these data provide compelling evidence for a central role of Notch signaling at the coordination of nutrient transport processes in the heart. These findings help to explain how pharmacological inhibition of Notch signaling, for example, in oncology could lead to heart failure. The findings also help to identify the signals and molecules involved in endothelial transport capacity and show how these could offer new targets for the treatment of heart failure.                                                 The next paper raises the prospect of new treatment options to combat ischemic heart disease and its progression to heart failure. Ischemic injury to the myocardium is known to trigger a robust, inflammatory response, which is an integral part of the healing process, although much effort has been directed at tempering the inflammatory response in hopes of achieving clinical gain. Major efforts have focused on individual cytokines, the complement cascade, and antibodies to adhesion molecules preventing leukocyte invasion.                                                 In contrast, relatively little effort has focused on macrophages. Although macrophage transformation is known to be crucial to myocardial repair, the events governing this transformation are poorly understood. In today's paper, co-corresponding authors of the trial in Hill, from UT Southwestern Medical Center, performed an elegant series of experiments and showed that release of DNA from necrotic tissue during myocardial infarction, triggered in macrophages a recently described innate immune response known as the GMP-AMP synthase-stimulator of interferon genes pathway or cGAS-STING pathway.                                                 This response in turn promoted an inflammatory macrophage phenotype. Suppression of the pathway promoted emergence of reparative macrophages, thereby mitigating pathological ventricular remodeling. These results therefore reveal for the first time, that the cytosolic DNA receptor, GMP-AMP synthase, functions during cardio ischemia as a pattern recognition receptor in the sterile immune response.                                                 Furthermore, this pathway governs macrophage transformation, thereby regulating post injury cardiac repair. As modulators of this pathway are currently in clinical use, these findings raise the prospect of new treatment options to combat ischemic heart disease and its progression to heart failure.                                                 Cigarette smoking is a well-known risk factor for atherosclerotic cardiovascular disease. However, less is known about the risk for heart failure. First author, Dr. Kamimura, corresponding author, Dr. Hall, from University of Mississippi Medical Center, and their colleagues investigated 4129 black participants without a history of heart failure or coronary heart disease at baseline in the Jackson Heart Study.                                                 They examined the relationship between cigarette smoking and left ventricular strength and function by using cardiac magnetic resonance imaging. They found that current cigarette smoking status, smoking intensity in terms of cigarettes per day, and smoking burden in pack-years, were independently associated with higher left ventricular mass, lower left ventricular strain, higher brain natriuretic peptides, higher BNP levels and higher risk of incident heart failure hospitalization in blacks.                                                 These relationships were significant after adjustment for coronary heart disease, suggesting mechanisms beyond atherosclerosis may contribute myocardial dysfunction and increased risk of heart failure in smokers. In summary, these findings suggest that smoking is associated with structural and functional left ventricular abnormalities that lead to heart failure in blacks and that smoking cessation should be encouraged in those with risk factors for heart failure.                                                 What happens to the risk modifying effects of exercise in individuals with increased genetic risk of cardiovascular disease. Drs. Tikkanen, Gustafsson, and Ingelsson from Stanford University School of Medicine performed the study in about 500,000 individuals from the UK Biobank and reported and compared the association's objective and subjective measures of fitness and physical activity with prospective cardiovascular disease events and all-cause death.                                                 They found consistent and robust inverse association, particularly between objective measures of fitness and physical activity and six cardiovascular outcomes and total mortality. Using genetic risk scores for coronary heart disease and atrial fibrillation, they showed that these inverse associations were present in each genetic risk category, suggesting that elevated genetic risk for these diseases can be compensated for by exercise.                                                 The knowledge that lifestyle choices have substantial effects on disease risk could encourage individuals to initiate a healthier lifestyle to reduce their overall risk. In the longer term, identifying subgroup space on genetic risk that benefit most from lifestyle interventions, could help personalize preventive strategies for chronic diseases.                                                 Well, that wraps it up for our summaries, now for our feature discussion.                                                 Today's featured paper deals with transcatheter aortic valve replacement, which we are all going to recognize has rapidly emerged as a treatment of choice in inoperable patients and, it's a reasonable alternative to surgical aortic valve replacement in high- and intermediate-surgical-risk patients. However, the success of this technology is in large part due to the rigor with which quantitative echocardiography by core laboratories has been used to assess the native and prosthetic aortic valve function.                                                 Today's feature paper gives us such important data from the REPRISE III trial, which compares the Lotus and the CoreValve transcatheter aortic valve in patients with high and extreme surgical risk. I'm so pleased to have the corresponding author, Dr. Federico Asch, from MedStar Washington Hospital Center, as well as our associate editor, Dr. Dharam Kumbhani from UT Southwestern. All right Federico, please help me here, so as a noninterventionist and a person who doesn't deal with all these different types of valves every day, please tell us what was the motivation of looking so closely at the echocardiographic data from REPRISE, because the REPRISE III trial results were already published? Dr Federico Asch:             The most interesting aspect of this analysis is really that there is a very methodic, blinded comparison of two different valves. The valve that is being tested and that the reason why Boston Scientific has sponsored the study, is the Lotus valve, the Lotus System is, if you want, a new valve that is not clinically approved in the United States yet, that basically, it's a completely repositionable bovine pericardial valve that comes in different sizes.                                                 The three sizes that were tested in here are what we would call the small, or 23 millimeters, the medium, 25 millimeters, and the large, 27 millimeters. Each patient, at the moment of randomization, or at the moment of inclusion, were randomized to the small, medium, or large Lotus valve vs the clinically approved CoreValve, which is a Medtronic product. Obviously, this is taken as the control group because this is one of the valves that is widely clinically available nowadays in the United States and worldwide.                                                 This is exactly the motivation here. On one side, to prove whether this valve was as good as CoreValve or not and whether it was as safe as the CoreValve as well, and that, the study was about. Every three patients that were randomized, two were randomized to the new valve, the Lotus, and one was randomized to the CoreValve.                                                 An important note to make here is because the control arm included clinically available valves at the beginning of the study, the previous generation of CoreValve was used and then about halfway through the trial, the Evolut valve was the one being used, so there's two different valves on the CoreValve system that were tested in this trial while Lotus was a single earlier generation valve. We focus here on the hemodynamic implications, that meaning, the gradients and the degree, if you want, of obstruction that these valves could have over time, and the amount of regurgitation that these two valves and how they compare to each other. Dr Carolyn Lam:                That's great. Could I ask if you had any hypothesis going in, because as I recall, the Lotus valve actually met the non-inferiority comparison, but it did have significantly higher rates of new pacemaker implantation and valve thrombosis, right? So, was that perhaps a hypothesis going in and what did you find? Dr Federico Asch:             So, the initial hypothesis of the trial overall was that this new valve was one that was designed to have less paravalvular regurgitation, which is something as you probably know, has been of significant concern in the cardiology world ever since the initial clinical trials for Tyler with Partner and CoreValves.                                                 Patients with more significant paravalvular leak did have worse outcome over time, so, one of the main goals of this valve itself, was to prevent that paravalvular regurgitation. So, that was the initial idea behind this product I would say, not just the clinical trial and obviously, this clinical trial tried to prove that, indeed, as I mentioned before, the primary effectiveness end point was mortality, disabling stroke, and paravalvular leak, the main driver on the difference between the two valves there was indeed a much lower paravalvular regurgitation on the Lotus valve compared to CoreValve.                                                 There was also lower stroke rate, but the most important difference was on the paravalvular aortic regurgitation. Of course, when you think of any of these devices, for them to be able to prevent paravalvular leak, they have to have some kind of skirt or cushioning around the valve, an adaptive seal, which in the case of the Lotus valve, that would prevent any flow around the stent, but one of the risks of that of course is that by trying to seal the valve, you're actually, you may be decreasing a little bit the effective orifice area, so it was actually very important to understand whether gradients with this valve were higher and whether the potential differences in the gradients did turn into any difference in clinical outcomes. Dr Carolyn Lam:                That is super clear now. What did you find? Dr Federico Asch:             I would say, the findings from a hemodynamic standpoint, we can briefly summarize them in two aspects of it. No surprise, the paravalvular leak was significantly lower for Lotus compared to CoreValve, and that was true for any of the three sizes, for the small, medium, and large size in all of them, the rate was significantly lower for Lotus. It was actually under 1% of the patients with moderate or higher paravalvular leak, as opposed to an average of 6.7% on the CoreValve, but on the other side of the spectrum, the gradients and the effective orifice area, and the dimensional index were all significantly better on the CoreValve compared to the Lotus.                                                 The bottom line is, we have two valves that each of them has a specific strength. On one side, Lotus has less paravalvular leak. On the other hand, CoreValve has a better gradient profile than Lotus. I would say in two lines, that's the findings of this study. We did take these findings further and compared among different valve sizes and we saw that these differences were consistent at each of the valve size, so if we would compare the small Lotus with the small CoreValve or the large Lotus with CoreValve, the findings were very similar.                                                 They were always significant, and what is important is that while there was a difference, both for paravalvular leak and for gradients and other hemodynamic parameters, the reality is that when it came to clinical outcomes, there was no significant difference among the two. Dr Carolyn Lam:                Dharam, you have to weigh in now as an interventional cardiologist, what does this mean to you. Dr Dharam Kumbhani:   First of all, Federico, congrats to you and Ted and the rest of the group. I think this is obviously a very important trial and I think this hemodynamics paper, I think definitely moves, helps understand the differences a little bit better, so I think this is a very valuable contribution. I think you said it exactly right. I think what is really interesting is that you have a significant introduction into the paravalvular leak, but yet you have, because of difference in valve design, one being annular vs the other being super annular, you have higher gradients with the Lotus valve compared with the CoreValve, so you wonder if the two differences can cancel themselves out in some way, because you don't see any difference in clinical end points at one year, and also, I guess, what we've learned from the Partner data and other CoreValve data is it would be really helpful to see how this evolves over time, whether there will be any late separation of the curves or just a long-term follow-up, whether that will still be important.                                                 I think that is the really interesting insight that we glean from this analysis. I want to make two other points. I think the other interesting thing about the design of the Lotus valve, and probably having such a great seal for the paravalvular leak reduction and having higher radial strength, I would think, at the annulus, I suspect that that's probably also the reason why the pacemaker rate is higher with this, compared with CoreValve, so it's almost 30% in this trial. About 20%, 18% already had an existing pacemaker, so particularly I guess, as we move to lower-risk population, I think that will certainly, balancing the two and deciding probably one valve doesn't fit everybody and we may have to have strategies to figure out which may be the best valve for a given patient based on this.                                                 The other point I'd like to make is the question about stents or valve thrombosis and I know that your group has been heavily invested in that research, because I know in the JAMA paper, there was a report of few valve thrombosis events and you also bring that home here in this hemodynamics paper. Is there anything you want to elaborate on that or any insights that you feel would be helpful for the next set of trials and next generation of the Lotus valve? Dr Federico Asch:             Yeah, you're bringing two very, very important points. Let me address the thrombosis one first. As you very well described, we have been working a lot on multiple different valves and understanding why this is happening. It's clearly something of concern. In this study in particular, we did not have data collected to detect subclinical thrombosis, which is what most of us have been talking mostly about over the last few years. The diagnosis of thrombosis here was not so clinical. These were patients that mostly, because gradients were going up, were detected. They were image ... there was one or two cases with TE and the other ones with CTs and then they were given anticoagulation and those results, and based on that is that the diagnosis of thrombosis was made. All those cases, nine cases, indeed, happen on the Lotus group. The CoreValve is one in that overall has shown to have lower rates of thrombosis in general and I'm not just talking about our own report. Our report was consistent with that.                                                 That may be something related to the fact that it's a super annular valve and the flow through the valve may be better, if you want, but we don't know that. The rate of thrombosis, again, clinical thrombosis, in this case, for the Lotus valve was 1.5%, which is still low, but it's impossible to compare to all those new reports that are coming out because those are mostly subclinical, which is not the case here.                                                 One could argue that if would have done CTs on every patient here at 30, 45 days, we would have found much higher rates in both valves, but we don't know that. We don't have the data to address that. Dr Dharam Kumbhani:   As I remember, almost all of them, I think seven out of eight of those reported, were in the 23 valve, right? They were not ... I think the larger valves ... Dr Federico Asch:             Exactly. There were nine cases overall, eight of them were on the small valve, on the 23 millimeters, and one was in the middle size, on the 25 millimeters. You are completely right. Dr Dharam Kumbhani:   I don't know what to make of that, but that was an interesting observation as well. Dr Federico Asch:             Yeah. It's interesting because when you look at reports of subclinical thrombosis, actually some of the reports suggest that this is more common in bigger valves than in smaller valves. Registries, I'm talking about, but that didn't seem to be the case here, but again, we need to understand the limitations. This was not a study geared towards detecting sub clinical thrombosis or thrombosis overall. These are just clinically reported cases that were analyzed thoroughly but they were triggered by some kind of clinical event, what's mostly an increase in the gradient.                                                 That's all that I would make out of the thrombosis. I think there is definitely more that we need to learn about it. We know that both CoreValve and Lotus have been reported to have cases of thrombosis, but in general, CoreValve seems to be of all the type of devices, the one with the lowest incidents. Dr Dharam Kumbhani:   Maybe your studies will help in understanding the influence of hemodynamic profile, patient-prosthesis mismatch, to the risk of thrombosis. I think the interactions are not well understood. I think that will be very interesting going forward. Dr Federico Asch:             Exactly. And the other comment that I wanted to make, Dharam, regarding your first impression about the pacemakers and the gradients, a couple of observations that I want to make out of that, one is that the difference in gradients between Lotus and CoreValve seem to be the highest early and then over months, that difference seemed to get smaller and smaller, still significant though, even at one year, but one could argue that if, as we continue following up these patients, maybe the difference starts getting smaller and smaller to the point that to become irrelevant, but we don't know that. That is just the impression that we get at looking at the curves over time.                                                 The pacemaker, obviously, as you can imagine, this is something that is of concern for everybody. It's a high rate, the newer Lotus generations are geared towards having lower paravalvular leak, like the head Lotus Edge and so we would expect that in the future that would be the case, but we don't know. The same way that it is important to mention that CoreValve has been addressing their initial concern, which was paravalvular leak.                                                 I mentioned before that the control arm in this clinical trial included CoreValve classic, earlier generations from roughly half of the patients, and the paravalvular leak in that group was a little bit over 10%, while the second group, which was the Evolut R had already a much lower rate of paravalvular leak, but was still significantly higher than Lotus, but was definitely better.                                                 I think what this points out to, is that all these devices are so early in their life, in their history, that all the efforts that each of these companies are making into fixing the specific problems that each of them have, really turn into a next generation that addresses more aggressively all these things. In the case of CoreValve, definitely the paravalvular leak is one and they are making very good progress in the care of Lotus, the permanent pacemaker is one and we expect in subsequent generations to improve as well. Dr Carolyn Lam:                It's been very enlightening for me and I'm sure for all our listeners. Thank you for joining us today listeners. Don't forget to tune in again next week.

Dr. Carolyn Lam:               Hello from the American Heart Association meeting in Anaheim. I'm Dr. Carolyn Lam, associate editor from Circulation at National Heart Centre in Duke National University of Singapore and I'm so pleased to be here with the Circulation team led by editor in chief Dr. Joe Hill, as well as with Dr. Laura Mauri, senior editor from Brigham and Women's Hospital, and Dr. Dharam Kumbhani, associate editor from UT Southwestern. Boy, we've got lots to discuss. I mean, I want to just first start with congratulating you, Joe. We have got quite a number of simultaneous publications here at the AHA. Dr. Joseph Hill:                  I appreciate that, Carolyn. Don't congratulate me. We have a team that is a privilege to work with. One of the initiatives that we launched right from the start was a desire to foster and shine a bright light on emerging science at the major meetings around the world. Often, that involves simultaneous publication.                                                 I'm proud to say that we have 11 simultaneous publications, a record for us here at AHA. Most of them are clinical trials. A few are clinical science, and two of them are young investigators who are competing in the various different competitions. We reached out to them a few weeks ago and offered them the opportunity to submit to us, of course with no guarantees, and our standard remains the same, but we promised that we would provide them with an external peer review. Two of them made it through the process and they will be simultaneously published with their presentations here in Anaheim. Dr. Carolyn Lam:               Wow, well you heard it. A record 11 simultaneous publications. We've got a lot to talk about. Let me just maybe group the topics a little bit. Let's start with talking about peripheral artery disease. I think there are at least three papers around that area, and then we'll talk about coronary artery disease, and almost focusing more on implementation science, papers, there are two there, and then of course we have to talk about heart failure. Dharam, could you start? Tell us about the FOURIER PAD trial. Dr. Dharam Kumbhani:  Yeah. It's very exciting to have clinical trials in the PAD realm. FOURIER PAD is certainly really well done sub-study of the FOURIER trial. As you remember, this was a landmark trial, which compared a PCSK9 inhibitor Evolocumab in two doses, two placebo. The overall trial was done in about 27,000 patients who were followed for a median of 2.2 years. In this trial, Marc Bonaca and investigators, they looked at the PAD subset, which were about 13% of the total cohort. Now, they specifically set out to look at how patients with PAD, during this trial and very gratifyingly, they also specifically assessed how patients with PAD did as far as limb events, not just cardiovascular events.                                                 At the outset, not surprisingly, patients with PAD had a higher risk of cardiovascular events by, I think it was about 60% higher for the primary end point compared with patients who did not have PAD. There was really no, in fact, modification by PAD in that the benefit of Evolocumab that we saw in the overall trial was preserved among the patients with PAD as well as those without PAD. However, because patients with PAD had higher event rates, the absolute risk reductions were higher in patients with PAD.                                                 Then, these investigators looked specifically at the incidents of major adverse limb events, which is a composite of acute limb ischemia, urgent revasc, and major amputations. What they show is that in the overall cohort, there is a 42% reduction in the risk of these major adverse limb events with Evolocumab compared with placebo. Obviously, the effect is significantly higher in patients with PAD. Although the benefit wasn't noted in the PAD subset specifically, the overall p-value for interaction was negative.                                                 One of the really exciting things about this paper is that just like investigators have shown a monotonic reduction in cardiovascular event rates with LDL reduction, similarly, the investigators show a reduction in limb events, which is dose related and the same way in a monotonic fashion with Evolocumab. I think this is really exciting and I think this will be a very important paper for the field. Dr. Carolyn Lam:               Yeah. Dharam, that was beautifully summarized but once you start talking about the peripheral artery disease and this lack of interaction on effects and so on, I think of the CANVAS trial results that were reported at this meeting too. If I could maybe briefly summarize what the authors did in this circumstance, they looked at the more than 10,000 patients in the CANVAS trial who were randomized into Canagliflozin versus placebo in diabetic patients but this time they looked at whether or not there was a difference in effect with the primary prevention cohort versus the secondary prevention.                                                 Primary prevention meaning those adults who had diabetes and risk factors but no established cardiovascular disease and the secondary prevention were those with peripheral artery disease, for example, and other established cardiovascular disease. The same thing, a lack of interaction, which I think is really important because it was the same sort of idea that the overall risk of cardiovascular events was lower in the primary prevention group. Looking at them as a subgroup alone, you didn't get the p-value that crossed the limit because the power was less in a lower risk group, but the lack of statistical interaction really gives us additional information, I think, that Canagliflozin and maybe the SGLT2s in general may be effective for primary prevention in diabetic patients. What do you think? Dr. Dharam Kumbhani:  Yeah. I mean, I think certainly, very interesting findings along those lines. As you pointed out, the event rates are much lower in the primary prevention cohort. All the confidence intervals overlap one, but because all the p-values for interaction for the three-point maze, the four-point maze, et cetera, one would say that there really isn't a difference between the primary and the secondary prevention subgroups. You would potentially have the same benefit in that subgroup as well. Dr. Carolyn Lam:               Fortunately or unfortunately, in that same study, they looked at the risk of amputations and there was a lack of interaction too for that meaning there was a higher risk of amputations with Canagliflozin versus placebo. That of course is a really hot topic now, isn't it? I just wanted to point out though, when you look at it in the primary prevention group, there are only 33 events. What do you think? It spells caution but further look needs to be done? Yeah. Contrast that with the EMPA-REG outcome PAD analysis. You want to tell us about it? Dr. Dharam Kumbhani:  Yeah. Once the Canagliflozin CANVAS findings came out showing a high rate of amputations with Canagliflozin, the Empagliflozin, the EMPA-REG outcome's investigators went back and looked at the PAD subset in EMPA-REG outcomes. This was about 20% of the total cohort. I will say that unlike FOURIER, which we just discussed, the ascertainment of amputations was not prospectively defined for this trial and it was really obtained from the CRF forms.                                                 However, having said that, it did not appear that amputation rates were higher with Empagliflozin. They did not break it down by the different doses but one assumes that the benefit is consistent between the two doses that they study. One would imagine the PAD patients would have a higher rate overall, which it was, but even in that group, it was about 6% over three years and there was really no difference between the patients who received Empagliflozin versus those who got placebo. Dr. Carolyn Lam:               That EMPA-REG outcome paper, I mean, interestingly, it was a research letter. Joe, you've been watching this whole field unfold right now and our journal has published so many good papers, including CVD REAL, all in this space. Could you comment on that a little bit and the research letter concept and the fact that we're publishing so many of these interesting papers in this topic? Dr. Joseph Hill:                  Well, Carolyn, as you inferred, this field is evolving very rapidly. Now, the interface between metabolic disease and diabetes and heart disease is blurring. Some of these diabetic drugs are really emerging as heart failure drugs, it looks like and so there's a great deal of interest in exploring that and trying to find underlying mechanisms. It's an incredibly exciting time. In parallel with that, we are publishing research letters now for papers where, again, our bar starts with validity. Our bar doesn't change but if it's a story that can be communicated with really one multi-paneled figure and an 800word text, then that is a nice bite-size piece of information that we can get out to our readership. We're publishing one or two a week now. Overall, it appears to be well received and I think it's an effective vehicle for conveying certain types of our content. Dr. Carolyn Lam:               Frankly, it's such a delight to read, isn't it? It's hard to write. I think the shorter, the harder to write but this just goes to show how equally important they are. Dr. Joseph Hill:                  Absolutely. Dr. Carolyn Lam:               That we're discussing it here. Well, let's go on to the next topic then, coronary artery disease. Regionalization of the care. I'll say that again, regionalization of the care. Would you like to comment on the two papers that are simultaneously being published? One would be the ACCELERATOR-2 trial. That's in the U.S. Then, a second from New Zealand, the ICare-ACS trial. Slightly different but- Dr. Joseph Hill:                  Well, that's exactly right. Often, we know what to do but we don't do what we know we need to do in medicine. The implementation of what we already know is an area of hot research and is an area that's evolving rapidly. These two studies, ACCELERATOR-2 here in the United States, focused on regionalization of the interface between EMS systems and EDs, how to get patients identified in the hospital to their device, whether it's a stent or a balloon pump or whatever it is. The first medical contact to device was the metric and by implementing what we already know, the AHA mission lifeline principles, these investigators were able to optimize this regionalization, so there wasn't so much variability across these 12 metropolitan regions. As a consequence, the time to first medical contact to device was shortened, and there was in fact a striking, maybe even surprising, mortality benefit. Dr. Carolyn Lam:               Exactly. That was striking to me too. Dr. Joseph Hill:                  From the street to the lab, another paper from New Zealand that you referred to called ICare-ACS focused on doing a better job in the emergency department with serial ECGs and serial high sensitivity troponins, risk stratification algorithms and they found that, again, by developing these clinical pathways within the ED, they were able to shorten the length of stay in the ED and the length of stay in the hospital. Dr. Carolyn Lam:               Yeah. I thought those were amazing and then also from different parts of the world, really strong public health messages as well. Laura, you take care of these ACS patients right on there. What did you think of these papers? Dr. Laura Mauri:                No, I agree. I think that we've, in the past, focused on science and focused on clinical trials but ultimately, none of that matters if we don't deliver the healthcare to the patient. I think this is just a growing field and I'm glad that we're emphasizing it in circulation. Dr. Carolyn Lam:               Absolutely. If we would now go to another area that is really increasing in prevalence throughout the world. Heart failure, and of course, heart failure with preserved ejection fraction. Dr. Joseph Hill:                  Your favorite topic. Dr. Carolyn Lam:               Congratulations, Laura on the paper that you're presenting, that is being presented at this meeting, the REDUCE LAP trial. Could you tell us a little bit more about that? Dr. Laura Mauri:                Sure. Yes, as you know, it's a really challenging field, heart failure with preserved ejection fraction. There aren't a lot of therapies that we have. We really don't have great medical therapy. This study actually looks at a medical device to treat patients. It really is a feasibility study, so it's a relatively small trial, just over 90 patients but it's randomized. We know in the device arena, as in all trials, how important randomization is but also blinding. This was actually a sham-controlled blinded trial really designed to look at this interatrial shunt device in patients who have an elevated wedge pressure.                                                 The REDUCE LAP stands for reduce left atrial pressure. That was the primary endpoint, was pulmonary capillary wedge pressure. This was not only looked at the safety, which showed that the device placement was very safe, but at the same time also looked at the proof of concept that by placing the shunt device, there was actually a reduction in wedge pressure over a period of exercise. It needs to be followed on. It's certainly just the first phase of trials but a pretty good standard with the sham control. Dr. Carolyn Lam:               Yeah, well, congratulations again. I mean, this follows … There was a previous publication of the single arm trial and now, this is the first randomized sham-controlled, and the results are consistent. It's a very difficult trial to carry out. HFpEF patients are notoriously difficult to recruit. Could you tell us a little bit about what it was like successfully completing this trial? Dr. Laura Mauri:                Yeah. Well, we had very enthusiastic centers and principal investigators, Ted Feldman and Sanjiv Shah. I think what it really required in this early phase was sites that were committed to characterizing the exercise physiology. The next stage of rolling this out to a broader number of sites and a larger number of patients to see if there's a clinical effect will really be more focused on the clinical endpoints and quality of life because ultimately that's the goal, is to improve symptoms in these patients. Dr. Carolyn Lam:               What I love about the design and the whole concept, it's so simple and elegant. We almost sometimes forget that HFpEF is heart failure, which means that by definition, there's raised filling pressures. It's hemodynamic at the end and this is just a simple concept of offloading the left atrium. That's so beautiful but it does come with some questions. Every time you mention this to someone, they go, “What about, I don't know, Eisenmenger's syndrome developing later?” The right side, volume overload, pulmonary hypertension, what about atrial fibrillation down the line? How about the safety parts of it? Dr. Laura Mauri:                Right, so the procedural safety was excellent but then I think you raise really important questions and these patients are still in follow-up but looking at the report here at this meeting, there was no pulmonary hypertension in excess in the shunt treated arm. The patient selection was towards patients who had higher wedge compared with right atrial pressure and among those patients, there was no evidence of RV overload. At least at this stage things look good to go on to the next step. Dr. Carolyn Lam:               That's wonderful and exciting. We definitely need a therapy for HFpEF. Joe, would you like to highlight any other trial? We have 11. We've discussed six. Dr. Joseph Hill:                  Tonight at the editorial board meeting, we will be saluting these two young investigators who are presenting their work in this competition and simultaneously publishing their work. We've invited these young investigators and their mentor and they will present a short talk to the editorial board dinner. It's an effort to salute and recognize these early career investigators, to congratulate them on outstanding work. We're pleased and privileged to publish it, so I'm particularly excited about that. Dr. Carolyn Lam:               Wow, Joe. That is great. Thank you. I didn't know that was happening either. That's fabulous. Dharam or Laura, any other highlights that you may want to mention in this meeting? Dr. Laura Mauri:                I think that it's just been a wonderful kickoff to the meeting. We've covered, I think, many of the really important trials so it's really exciting to be able to see the work in print. Dr. Carolyn Lam:               That's great, and to discuss it as well. Dr. Dharam Kumbhani:  Yeah, I agree. This is really exciting and hopefully, we can keep growing from strength to strength every year. Dr. Carolyn Lam:               Yep. You heard it right here everyone. We are going to grow from strength to strength under your leadership and with this great team, so thank you very much for joining us today.  

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.                                                 Our journal this week features novel data informing the choice between conscious sedation and general anesthesia for transcatheter aortic valve replacement. A very relevant discussion for those of us who see these patients. Stay tuned, that's coming right up after these summaries.                                                 Subclinical hyperthyroidism is known to be associated with an increased risk of atrial fibrillation, but the association with thyroid function in the normal range or subclinical hypothyroidism is unclear. That is, until today's study, which shows us that variation in thyroid function within the normal range is associated with atrial fibrillation.                                                 First author, Dr. Baumgartner, corresponding author, Dr. Rodondi and colleagues from University of Bern in Switzerland, conducted a systematic review and obtained individual participant data in more than 30,000 participants from 11 prospective cohort studies that measured thyroid function at baseline and assessed incident atrial fibrillation, which occurred in 8.6% of individuals.                                                 They found that in youth thyroid individuals, there was a significant increase in the risk of atrial fibrillation with increasing free T4 levels within the reference range. Risks did not differ significantly by age and sex.                                                 Conversely, there was no association between TSH levels within the reference range, or subclinical hypothyroidism and the risk of atrial fibrillation. Thus, free thyroxin levels might add to further assessment of atrial fibrillation risks. Further studies are needed to investigate whether these findings apply to thyroxine treated patients.                                                 The next study provides insight into how exercise promotes metabolic remodeling in the heart. First author, Dr. Gibb, corresponding author, Dr. Hill and colleagues from University of Louisville, use radiometric, immunologic, metabolomic and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise.                                                 They found that in the heart, glucose utilization via glycolysis was reduced during exercise and in the early recovery period after exercise. Low rates of myocardial glycolysis were sufficient to activate gene programs that instigate physiologic cardiac growth. Metabolic inflexibility of the heart, such as occurs in heart failure and diabetes, was sufficient to diminish mitochondrial function.                                                 Phosphofructokinase mediated changes in metabolism appeared to regulate genes involved in processes critical for metabolic remodeling, transcription, cell division, differentiation, cell proliferation and contraction. Thus, this study provides important preclinical evidence, showing how exercise-induced changes in glucose metabolism may promote physiologic cardiac growth.                                                 The next study addresses the question of whether antiarrhythmic drugs are safe and effective when non-shockable rhythms evolved to shockable rhythms during resuscitation for out of hospital cardiac arrests. In this study from first and corresponding author, Dr. Kudenchuk of University of Washington and his colleagues, patients who initially presented with non-shockable out of hospital cardiac arrests were randomized upon subsequently developing shock refractory VF or VT to receive amiodarone, lidocaine or placebo by paramedics.                                                 The primary outcome was survival to hospital discharge, with secondary outcomes, including discharge functional status and adverse drug-related effects. The authors found that outcome from non-shockable turned shockable out of hospital cardiac arrest was poor, but not invariably fatal. Though not statistically significant, point estimates for survival showed a trend to greater survival after amiodarone or lidocaine than placebo without increased risk of adverse effects or disability. Together, these findings may signal a clinical benefit that invites further investigation.                                                 The final study provides experimental data supporting the importance of a novel Cardiokine governing the local environment in infarcted hearts and determining the fate of implanted cells. This novel Cardiokine is C1q/tumor necrosis factor-related protein-9, or CTRP9, which is a novel pro survival Cardiokine that is significantly down regulated after myocardial infarction.                                                 In today's study by co-first authors, Drs. Yan and Guo and co-corresponding authors Drs. Ma and Wang from Thomas Jefferson University in Philadelphia, mice were subjected to myocardial infarction and treated with adipose-derived mesenchymal stem cells, CTRP9 or their combination. The authors found that administration of adipose-derived mesenchymal stem cells alone failed to exert significant cardio protection.                                                 However, administration of these cells in addition to CTRP9 further enhanced the cardioprotective effect of CTRP9, suggesting a synergistic effect. CTRP9 promoted adipose-derived mesenchymal stem cell proliferation, survival, migration and attenuated cardio myocyte cell death by signaling mechanisms that included binding with N-cadherin, activation of ERK, MMP9, and ERK-Nrf2 signaling and upregulation or secretion of antioxidative proteins.                                                 In summary, these results suggest that CTRP9 is a Cardiokine critical in maintaining a healthy microenvironment facilitating stem cell engraftment in infarcted myocardial tissue. Well, that wraps it up for your summaries, now for our feature discussion.                                                 Conscious sedation is very frequently used during transcatheter aortic valve replacement, or TAVR, but with limited evidence as to the safety and efficacy of this practice. Well, that is until this week's journal and this feature paper. We're so lucky to have with us the corresponding author, Dr. Jay Giri from Hospital of University of Pennsylvania, to discuss his novel findings, as well as Dr. Dharam Kumbhani, Associate Editor from UT Southwestern.                                                 Jay, tell us your study findings and how this really helps us to characterize anesthesia choice and clinical outcomes of at least U.S. patients undergoing TAVR. Dr. Jay Giri :                        We looked at 11,000 patients treated over a 15-month period in 2014 and 2015 with percutaneous transfemoral TAVR. Notably, this was a time period that was identified as the start of the era of conscious sedation for TAVR in the United States.                                                 Also, this five quarter period that we looked at represented a time of relative technological stability where only two valve types, the Sapien XT and original Medtronic CoreValve were being used in America.                                                 Looking at that 15-month period when conscious sedation was first being used in TAVR, we elected to compare those patients to a propensity matched group of patients who underwent TAVR by, what at that time was, the more traditional approach of general anesthesia.                                                 Our primary outcome within hospital mortality, because we had complete followup for this outcome. We also looked at 30-day outcomes for which we had about 90% followup. What we discovered was actually an associated reduction in mortality, an absolute reduction of about 1% in the patients who were treated with conscious sedation.                                                 We also noted that they had modest decreases in the hospital length of stay, as well as significant decreases in the rates of ICU length of stay and the rates of pressor or inotrope use during the procedure. Obviously, the most provocative of the findings was the fact that we seemed to discover, after propensity matching a slight improvement in in-hospital mortality that held true at 30 days, as well. Dr. Carolyn Lam:               Thank you, Jay. What important findings ... I mean, mainly because, we really didn't have much data, did we? About conscious sedation and TAVR before this. Now, it's observational data, and I suppose the question always becomes what about bias by indication? More well patients get selected for conscious sedation versus general anesthesia, perhaps? Or even the other way around. Could you elaborate a little bit on how you think that may have impacted results and the measures you took to look at that? Dr. Jay Giri :                        I think it was something that we were highly aware of and I also have to give credit to Dr. Kumbhani and the editorial staff at circulation for pushing us on that issue of selection bias for the two procedures. The obvious concern here, when you saw that there was a potential mortality reduction with conscious sedation patients, was that perhaps the conscious sedation patients actually represented a healthier cohort to start with, or they were perhaps treated at centers that were more highly experienced and by operators that were more highly experienced with TAVR in general.                                                 We tried to account for this in a number of different fashions. The first, as we mentioned, was with an inverse probability treatment weighted analysis that accounted for 51 co-variants that were balanced between the groups. Additionally, we did adjust for site characteristics and utilized a hierarchical method technique to take into account both the experience of sites and operators.                                                 Finally and most importantly, we performed what's called a falsification end point analysis in a postdoc fashion to verify that it looked like other outcomes outside of things, like mortality, length of stay, things we would expect to be influenced by sedation type, ended up being equal between the two groups. Falsification end point analysis represents, essentially, a negative control. You're supposed to theorize for potential outcomes that you would think would not be influenced by your intervention. In this case, those outcomes we theorized were vascular complications, major bleeding and pacemaker implantation, which we theorized would not be influenced by sedation type. In fact, we discovered that those outcomes were similar after adjustment, even though they had some differences before adjustment. Dr. Dharam Kumbhani:  Jay, I want to congratulate you and your team on this paper. You guys really picked a very important topic to look at and then you jump ... as you outlined, you jumped through a lot of statistical hoops and try to really provide evidence for a field in which a randomized controlled trial is probably going to be just logistically probably hard to conduct, just given the sample size requirements, which also you've provided in your discussion.                                                 I think all the metrics that you looked at as far as utilization of therapies and length of stay, things like that, I think many people believe that and you were the first one to systematically evaluate and show that.                                                 As you alluded to, I think that mortality, and Carolyn mentioned that, as well. I think the mortality findings are very interesting. Again, it's always hard when you have observational data to really put a lot of stock into that and you guys, as you outline, looked at so many different ways of doing that.                                                 Again, I guess, observational data are always inherently going to have that limitation, no matter what statistical rigor we put them through. They were definitely very thought-provoking and, as you outlined, it's definitely come at the right time as the field is exploding and more and more centers are getting facile at it.                                                 The other thing that you mentioned, but which I want to make sure that people fully understand is that you also provided a very elegant analysis looking at site volumes, because traditionally the sites that are doing conscious sedation have done a number of TAVR's before and there is a very clear cumulative volume outcomes association, for TAVR.                                                 By accounting for the totality of experience, so you adjusted for the cumulative volume that sites have been doing this, so these are not just the high volume, high throughput centers, which have a lot of experience doing 150, 200 TAVR's a year, that thereby have really good outcomes by virtue of being expert, both as operators and as sites, but rather potentially something that is related to conscious sedation aspect itself. You guys really stepped up and provided a very elegant analysis to try to dissociate the two issues here. Dr. Carolyn Lam:               Dharam, and you just provided a very elegant explanation of the thought processes that were going on with our editors about this paper. I join you in congratulating Jay. Just a question. This is the best available evidence now, what are we going to do about it? I mean, Dharam, you're an inventionist, what now? Dr. Dharam Kumbhani:  The issues were not so much related to efficacy, initially. The initial concerns were related to safety, and Jay's paper clearly addresses that. Then, in addition to that, it says, "Well, it's not just that it's a safe procedure, but it's also effective with potential patient level and hospital level benefits from having a robust conscious sedation program."                                                 I guess the one question that I have about conscious sedation and, Jay, I would love to hear your thoughts on this, as well, is it is possible but it is usually not done, TEE's or transesophageal echos are typically not done when you're doing conscious sedation. It is possible, as I said. As you move towards lower risk patients, on the one hand, these would be ideal patients for conscious sedation because then it's almost like a day procedure, in some ways for them.                                                 But on the other hand, the fidelity of being able to look for even small paravalvular leaks, things like that, may be harder with a transthoracic echo. I don't know, as we expand towards the oldest populations, whether we'll see a greater adoption of conscious sedation, or whether there'll be some scaling back. Dr. Jay Giri :                        Two points on that. The first is, I totally agree that it's relatively unusual for a transesophageal echo to be performed in the setting of conscious sedation. There's no question, secondly that transesophageal echo allows for the most rigorous evaluation of paravalvular leaks.                                                 It is striking, though, that the rates of paravalvular leaks, due to technological improvements to the valves, are significantly improving. Even since the time of our study two years ago, a new generation of valves is consistently coming out with leak rates in pretty well-conducted analyses that are in the low, single digit percentages for moderate leak or more.                                                 Part of I think the move towards conscious sedation, even initially and especially as we go forward, is predicated on the fact of continuing technological improvements that essentially almost solve the leak problem.                                                 I think it's true that there's always going to be a very small minority of patients that are stuck with concerns about paravalvular leak at the end of their TAVR procedure. For those who have moderate or greater leak, I think that the threshold for escalating care, even to intubation and TEE to evaluate that leak, I think should be relatively low in a lower risk population.                                                 However, I think the point that you bring up about the potential harm of trace or trivial leaks, or mild leaks, which may not be perfectly interpreted with transthoracic echo and aortograms and [inaudible 00:16:41] assessments at the time of the valve placement. It's something we're going to have to keep a close eye on.                                                 From a practical standpoint, I believe this train has left the station. Totally unscientific, but around the time they released the paper online. I just shot out a poll on Twitter and got about a couple of hundred responses from folks, what they're doing now.                                                 Now, Twitter certainly, probably doesn't represent the average transcatheter valve operator in the world, but I was surprised to see that over 70% of the respondents favored a conscious sedation approach at this point in time, which obviously is much higher than what we saw in our paper from two years ago. Dr. Carolyn Lam:               Well, audience, I'm sure you enjoyed that. Thank you for joining us today. Don't forget to tune in again next week.

  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 Centre and Duke-National University of Singapore. In just a moment, we're going to be discussing new results of the pioneer trial, and the patient with atrial fibrillation who undergoes intracoronary stenting, a familiar conundrum. What's the role of NOACs? Is there still a role for full-dose triple therapy with warfarin? First, here's your summary of this week's journal. The first paper tells us about the clinical impact of left atrial appendage closure. Dr. Melduni and colleagues from the Mayo Clinic in Rochester, Minnesota, studied 9,792 patients undergoing bypass or valve surgery between 2000 and 2005. They used propensity score matching to estimate the association of left atrial appendage closure with early post-operative atrial fibrillation- defined as atrial fibrillation within 30 days of surgery- ischemic stroke, and mortality. They found that after adjustment for treatment allocation bias, left atrial appendage closure during routine cardiac surgery was significantly associated with an increased risk of early post-operative atrial fibrillation, and did not influence the risk of stroke or mortality. They therefore concluded that it remains uncertain whether prophylactic exclusion of the left atrial appendage is warranted for stroke prevention during non-atrial-fibrillation-related cardiac surgery. The next study provides pre-clinical evidence that genes on sex chromosomes may contribute to the sexual dimorphism of abdominal aortic aneurysms. That is, we well know that abdominal aortic aneurysm is a male-predominant disease. Now, in this paper, by first author Dr. Alsiraj, corresponding author Dr. Cassis and colleagues from the University of Kentucky, female LDL-receptor-deficient mice, with an XX or XY sex chromosome complement, were infused with angiotensin II for 28 days to induce abdominal aortic aneurysms. DNA microarrays were performed on the abdominal aortas, and to mimic the males, the female mice were administered a single dose of testosterone. They found that an XY sex chromosome complement, in phenotypic females, profoundly influenced aortic gene expression profiles and promoted abdominal aortic aneurysm severity. When XY females were exposed to testosterone, aneurysm rupture rates were striking. The mechanisms for augmented abdominal aortic aneurysm severity in XY females included increased inflammation, augmented matrix metalloproteinases, and oxidative stress. These results, therefore, demonstrate that genes on the sex chromosomes regulate aortic vascular biology and contribute to sexual dimorphism of aortic abdominal aneurysms. Sex chromosome genes may therefore serve as novel targets for sex-specific abdominal aortic aneurysm therapeutics. The next two studies shed light on the mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism. In the first study, Dr. Watts and colleagues from University of Western Australia carried out a two-by-two factorial trial, of high-dose atorvastatin versus evolocumab on stable isotope tracer kinetics in 81 healthy, normal lipidemic, non-obese men. They found that both atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL apoB, IDL apoB, and LDL apoB. On the other hand, evolocumab, but not atorvastatin, also decreased the production rate of IDL apoB and LDL apoB. The reduction of LDL apoB and LDL cholesterol was significantly greater with a combination versus either mono-therapy. In summary, they found that in healthy, normal lipidemic men, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism, and by reducing IDL and LDL production. The latter effects are incremental to statins. The second paper to deal with this topic comes from Dr. Ginsberg and colleagues from Columbia University in New York, who studied 18 participants, this time 10 of whom were women, who completed a placebo-controlled two-period study, receiving two doses of placebo followed by five doses of alirocumab. These authors found that alirocumab decreased LDL cholesterol and LDL apoB by increasing IDL and LDL apoB fractional clearance rates, and by decreasing LDL apoB production rates. These results were consistent with increases in LDL receptors available to clear IDL and LDL from the blood during PCSK9 inhibition. These two papers are discussed in a beautiful accompanying editorial by Dr. Chris Packard from University of Glasgow. In his editorial entitled "Unpacking and Understanding the Impact of PCSK9 Inhibitors on Apolipoprotein B Metabolism." Those were your highlights! Now for our feature discussion. Today we are going to be discussing one of the most common conundrums in all of cardiovascular medicine, and that is the care of patients with atrial fibrillation who also need percutaneous coronary intervention. Of course, both dual antiplatelet therapy and oral anticoagulation therapy would be indicated to reduce the risk of stent thrombosis and thromboembolism in atrial fibrillation, respectively. However, with the intensification of the anti-thrombotic regimen, there is the inevitable trade-off with more bleeding. Now, to discuss this, we have the first and corresponding author on a very novel study of the pioneer trial, and that is Dr. Michael Gibson, from Harvard Medical School and Beth Israel Deaconess Medical Center. We also have the editorialist for this very exciting paper, Dr. Deepak Bhatt from Brigham and Women's Hospital, and finally, we have Dr. Dharam Kumbhani, associate editor from UT Southwestern. Welcome, gentlemen! Dr Deepak Bhatt:           Thank you. Dr Michael Gibson:          Thanks. Dr Dharam Kumbhani:   Thank you. Dr Carolyn Lam:                So, Michael, could I start with you? This is a sub-study of the pioneer study. Could you tell us how this is different from the primary results, what were you looking for, and what you found? Dr Michael Gibson:          As you know, as [inaudible 00:07:40] said, we have a lot of bleeding with conventional triple therapy, and we used two regimens to try and reduce that bleeding. One was a reduced dose of rivaroxaban, 15 milligrams, plus thienopyridine. The other strategy was baby dose rivaroxaban, 2.5 milligrams twice a day, plus DAPT. What we found in the overall study was a significant reduction in bleeding- from, say, 26.7% down to 18% for riva plus DAPT- that's the baby dose plus DAPT- and down to 16.8% for the 15 milligrams of riva plus the thienopyridine. You'd have to treat about 11 to 12 patients to prevent one significant bleeding event. That's the mainstay. What we found in this very, very important sub-study is that that was associated with reduction in hospitalization. All-cause hospitalization was reduced, and cardiovascular hospitalization went down from 28.4% to about 20% for the two regimens. Bleeding with hospitalization went down, from 10.5% to about 6%. At the end of the day, you'd only have to treat 10 to 15 people to prevent one hospitalization, so from a health economic perspective, and from a patient viewpoint and hassle perspective, this was very important. Dr Carolyn Lam:                In fact, Michael, I would say from a clinician-cardiologist perspective, these results are really very applicable. In fact, I really like, in the accompanying editorial, what Deepak wrote, that it may be one of those rare occasions where a sub-study provides very clinically meaningful information compared to the primary study. Deepak, would you like to elaborate a little bit more about that? Dr Deepak Bhatt:             Sure. A really great point that you've raised. It wasn't, in fact, a sub-study we're talking about in Circulation. It was an analysis from the overall trial, looking at a different endpoint than the primary endpoint, the hospitalization, and the composite of hospitalization and mortality. I think that's a very important endpoint. If it were a heart failure trial, for example, that's the endpoint everyone would hone in on- mortality and hospitalization. The fact that that was significantly reduced, I think, is very clinically meaningful. Mike mentioned the economic implications, which for sure are there, by reducing hospitalizations and re-hospitalizations. The impact on cardiovascular hospitalizations- the reduction there- I find particularly remarkable. The reduction in bleeding, of course, is good, and in its own right has a great deal of value, but the additional reduction in cardiovascular hospitalizations, I think, is quite reassuring for those that are worried about the efficacy of the two experimental regimens that he and his colleagues studied. Sure, the trial's not powered in each individual sub-group for rare events like stroke, but the fact that CV hospitalizations are not increased, and in fact reduced, tells me that this is a winning strategy or strategies. Dr Carolyn Lam:                Right. Michael, another issue, though- this is open label, and I suppose one of the criticisms could be that there is a bias for clinicians managing patients on the traditional Vitamin K antagonist to maybe hospitalize patients more for some reason. What is your response to that? Dr Michael Gibson:          That is always the criticism of an open label trial, but again, the events were adjudicated, and for the heart events, that's done in a blinded fashion, so it's reassuring that there was a blinded assessment of the heart events. Dr Carolyn Lam:                True. How about comments on generalizability? I mean, what do you think? Trial setting, real world ... Dr Michael Gibson:          Yeah, I think that's one of the advantages. This was very much a real-world kind of study. It was truly done throughout the world. We had a very broad entry criteria. Anyone who was getting a stent put in- you didn't have to have ACS, although about half the patients did. The only real exclusive criteria was you couldn't have any bleeding or be profoundly anemic. You couldn't have a stroke or [TIA 00:11:58] in the past. Other than that, it made real-world practice in a lot of ways. Dr Dharam Kumbhani:   This is Dharam. If I may ask both the other people on the call, is ... Rivaroxaban is not FDA approved, in these doses, for use. I'm wondering if they might provide some comment, given the benefit that we see in this trial, overall, what their thoughts are and what the next steps might be. Dr Carolyn Lam:                Sure. Maybe Michael, then Deepak? Dr Michael Gibson:          Yeah, that's a good point. It is important to point out that you'd need to check the prescribing information in your country. In some countries- I think it's about 54 countries- the 2.5 milligram dose is available. It is approved for ACS, but is not approved for a-fib. Then, you have a dose of 20 milligrams that's approved worldwide for a-fib, but there are some countries- it's important to note, in some countries, 15 milligrams is the full dose that's approved- say, in Japan and Taiwan. There are Japanese studies showing that 15 milligrams was not only safer than warfarin, but more efficacious than warfarin in a trial like J-ROCKET. You're right, the 15 milligram dose is available in the US- it's approved for renal insufficiency, but at this time, it's not labelled for the ACS or stented patient. But again, physicians are at liberty to look at this data, which is the first real data that we have to guide decision-making in this setting, and they're at liberty to make their own choices. Dr Deepak Bhatt:             Yeah, I would agree with that assessment, and emphasize ... Like Mike said, it's an international audience for Circulation, so I would say, look in your own country, and in many parts of Europe, the 2.5 milligram rivaroxaban dose is available and approved for ACS, and could therefore be used for this purpose, though not strictly falling within the label indications. In the US, there's the 15. I think, if I just answer the previous question, the results are very generalizable, and for doctors that critique that point, I'd say, "Why didn't you enroll your patients in the trial?" There's the RE-DUAL as well, that's ongoing, with dabigatran, AUGUSTUS with apixaban, and I'm missing one that's also ongoing as well, I think, but there are four different trials that are out there. The Pioneer was the first to report ... Dr Carolyn Lam:                I think you're thinking of the Entrust AF-PCI with Edoxaban. Dr Deepak Bhatt:             The most recent one, yes. I forgot the acronym, there. If people are really thinking that the results don't apply to their patients, well, there are trials that are ongoing. Enroll your patients. But to say, "Oh, my patients, I'm not going to enroll them in the trial," and then say, "The results aren't generalizable," I always find that an odd thing. I think the results are very generalizable. The one word of caution I would say, though, is to make sure to renally dose, as was done in the trial. That is, there was a downward adjustment in dose from the 15 milligrams to the 10. In real life, we've seen in registries with NOAC use, whether it's rivaroxaban or any of the others, a lot of times, the renal function is not carefully monitored in those patients that are on the fringe in terms of their renal function, and that's the one situation NOACs can backfire, where the dose isn't corrected for their degree of renal dysfunction. Other than that one caveat, I think the results are quite generalizable. Dr Carolyn Lam:                Excellent comments. We should wrap up soon, but not before I want to ask Dharam. Thank you for managing this beautiful paper. What, to you, is the take-home message for clinicians out there? Dr Dharam Kumbhani:   Yeah, it was an absolute honor and delight to manage this, and I think the paper's great. The editorial's great. It's gotten a great response. I think the take-home message is that this is a very clinically relevant question, and a very clinically relevant trial, and it shows that the needle will be moving towards using non-VKA-based agents, especially in patients such as this, who have both a-fib and PCI. I think this is very exciting space, a very important space. This trial suggests that if you use the strategy rivaroxaban low dose, with or without a DAPT, that it is safer, both in terms of mortality and bleeding, compared with what is traditionally being used with warfarin plus DAPT. I think this was a very, very exciting trial. Dr Carolyn Lam:                Indeed, and congratulations to all three of you. Thank you so much for joining me on Circulation On The Run. Thank you, listeners, for joining us too, and don't forget to tune in next week.  

  Dr. 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 in Duke National University of Singapore.     Today we will be discussing the first multinational study looking at per-cutaneous device closure of peri-valvular leaks, a topic I'm certain you'll recognize as rapidly developing in cardiology, but first, let me fill you in on the highlights of this week's journal.     The first paper is a translational study telling us that when transfusing stored red blood cells for hemorrhagic shock, cold transfusing hemopexin and heptoglobin may be beneficial. This study is from first author Dr. Graw, and corresponding author Dr. Zapol and colleagues from the anesthesia center for critical care research at Massachusetts General Hospital and Harvard Medical School.     These authors reasoned that erythrocytes undergo progressive deleterious changes during storage. Such that, the transfusion of long-stored, packed red blood cells increases plasma levels of cell-free hemoglobin and heme. These are toxic breakdown products of hemolyzed erythrocytes.     Now, mammals usually synthesize the scavenger proteins: heptoglobin and hemopexin, which bind these toxic extracellular hemoglobin and heme, respectively. The authors therefore, tested the concept of cold transfusion of heptoglobin and hemopexin along with stored red blood cells in their murine remodel of hemorrhagic shock.     They first showed that resuscitation with long-stored, packed red blood cells produced a higher mortality, higher plasma hemoglobin levels, hemoglobinuria, kidney injury and diffused tissue inflammation, compared to resuscitation with fresh, packed red blood cells. However, when resuscitating hemorrhagic shock with stored red blood cells co-infused with either exogenous human hemopexin or heptoglobin, there was an increased survival and decreased tissue inflammation. Furthermore, co-infusion of heptoglobin with the stored red blood cells, prevented hemoglobinuria and kidney injury. These animal model data warrant further assessment in clinical conditions of severe hemolysis.     The next study suggests that sickle cell disease, although primarily a blood disease, may also be considered a vascular disease. This is a paper from co-authors Dr. Ranque and Menet from the University Paris Descartes in France, and describe results from the CADRE study. That is, the heart arteries and sickle cell study, which is the World's largest ongoing cohort of sickle cell disease that prospectively recruited more than 3,700 patients with sickle cell disease and 950 healthy controls from Cameroon, Ivory Coast, Gabon, Mali, and Senegal.     The authors found that mean carotid femoral pulse wave velocity was lower in patients with sickle cell disease, compared to controls and lower in specific hemoglobin phenotypes compared to others. Augmentation index, corrected for heart rate, also increased more rapidly with age in the patients with sickle cell disease, compared to controls, and was higher in patients than in controls. Both carotid femoral pulse wave velocity and augmentation index were independently associated with the glomerular filtration rate and osteonecrosis.     Augmentation index was also associated with stroke, pulmonary hyper-tension and priapism. Whereas, carotid femoral pulse wave velocity was also associated with microalbuminuria. These findings really under-score the association between sickle cell disease and vascular abnormalities and complications. The prognostic value of these vascular indexes will be assessed during the follow-up of these patients.     The next paper is a basic science paper suggesting that after sudden cardiac arrest, normalizing calcium cycling, may be a novel approach to improved post-arrest myocardial function. This paper is from co-corresponding authors Dr. Woods, from the Palo Alto Medical Foundation and Dr. Ashley from Stanford University in California.     These authors developed a rodent model of cardiac arrest using ECMO resuscitation. They used a genetically encoded calcium sensor in a novel fiber optic catheter imaging system to observe calcium-induced calcium release in-vivo before and after resuscitation. They then isolated cardiomyocytes from this model and assessed a mechanical load and calcium cycling simultaneously, using the micro-fiber carbon technique.     The main finding was of potentiation of calcium-induced calcium release in the post-arrest situation that began in-vivo and was mediated by activation of the calcium calmodulin kinase 2 or CaMKII. Since they also observed that oxidated stress and aldehydic adduct formation were high post arrest, they further tested a small molecule activator of aldehyde dehydrogenase type 2, known as Alda-1, which reduced oxidative stress, restored calcium and c CaMKII homeostasis and improved cardiac function in post-arrest outcomes in-vivo.     These findings are significant for their potential translational application in post-sudden cardiac arrest, a condition which is really known to have a high mortality.     The next study reports the results of the DOCTORS Study, standing for Does Optical Coherence Tomography Optimized Results of Stenting. This paper is from Dr. Meneveau from the University Hospital Jean Minjoz and colleagues. The DOCTORS Study is the first randomized control trial testing optical coherence tomography via OCT guided PCI to standard fluoroscopy guided PCI in 240 patients with non-ST-elevation and acute coronary syndromes.     The first finding was that OCT results directly impacted physician decision making, leading to a change in procedural strategy in half of the cases in the OCT guided group. The primary end-point of functional results of PCI, as assessed by post-PCI, FFR, was modestly improved in the OCT guided group compared to fluoroscopy alone. This improvement appeared to be explained mostly by optimization of the stent expansion. The benefit was obtained at the cost of a longer procedural and fluoroscopy time and more contrast use, but without an increase in peri-procedural myocardial infarction or kidney dysfunction.     These findings of the DOCTORS study add to the accumulating body of evidence supporting a potential benefit of OCT to guide PCI procedures in acute coronary syndrome. Additional prospective studies with clinical endpoints are warranted. These issues are discussed in an excellent accompanying editorial by Dr. Wijns and Dr. Pyxaras.     This brings us to the end of our summaries. Now for our feature paper.     Our featured paper today discusses a problem that we've actually created and that is para-valvular leaks following surgical valve replacement, and we're specifically discussing the role of percutaneous device closure exploring the first multi-national experience form the United Kingdom and Ireland and I'm here with first author, corresponding author as well, Dr. Patrick Calvert from Papworth Hospital in the United Kingdom. Welcome Patrick.   Dr. Calvert: It's a great pleasure to be here, thank you for inviting me.   Dr. Lam: Joining us also is Dr. Dharam Kumbhani, associate editor from UT Southwestern, hi.   Dr. Kumbhani: Hi Carolyn, thanks for having me.   Dr. Lam: Let's get straight into this. It's a problem we've created. How common is it? Why should we care about talking about perivalvular leaks?   Dr. Calvert: You know Carolyn, this is actually quite a common problem. The series we know from previous publications around 5-17% of surgical valves develop leaks. We know in the early experience of TAVR that there was quite a problem with leak, although more recent iterations that's less of a problem. There's a lot of patients out there that have this problem. It's a difficult problem to treat because these are, by definition, high-risk patients and re-operation is not such an inviting thought for them to have. This is something that needs may be a different solution than re-operation.   Dr. Lam: Could you tell us what makes your series special?   Dr. Calvert: Yes, so let's talk about the other series first of all. We had a fabulous series published in 2001 from the Mayo Clinic. That was a single center of excellence where they are really great at doing the procedure, but they gave us great insight of a master class, really if you like, if I had to do the procedure. What is different about our paper is that it's like a real-world experience. It's all the centers that contributed in the United Kingdom and Ireland. It's 20 centers over an 11 year period, in total 308 procedures. It's, if you like, a warts-and-all approach to it. It think that's one way it's a little different.     I think another way that it definitely stands out is that we are fortunate enough in Europe to have licensed or CE-mark, a number of oblong devices that are a little different in shape. What we do know about these holes is, they tend to be crescentic in shape or at least longer then they are wide. The problem is, if you try to put a circular device in an oblong hole, it's not going to work.   Dr. Lam: Which types of perivalvular leak are you talking about here?   Dr. Calvert: We have approximately 50/50 split between the aortic surgical valve and the micro-surgical valve. Then, about 5% were TAVIs or TAVRs. Then we had a small number of pulmonic valves and one or two around angioplastic rings, so that's the proportions. We had about 57% mechanical valves and 37% bio-prosthetic valves.   Dr. Lam: Wow, first congratulations. That is really important information. I can already imagine. I see those patients too. Dharam, as an interventional cardiologist. What is your take on it. Especially this mention of the oblong devices? They are not FDA approved, so they won't be in the United States, but what did you think of that, managing this paper?   Dr. Kumbhani: I think this is a very tricky subset of patients to treat. As Patrick and his group have shown, that the rates of success can be very high. As you point out, we don't have all the devices that they have in the U.S. A lot of us who do this use more circular devices but they're flexible. The feeling is that they tend to fit in with whatever geometry of the leak is. I do think it would be interesting, and probably more appropriate to have devices that are shaped like these holes are. As Patrick mentioned, they're usually crescentic, or certainly not round.   Dr. Lam: As a non-interventional cardiologist, I didn't realize it was very intricate. Tell us about your main findings.   Dr. Calvert: Our principle findings, and what I think is the most important thing is that, if you're going to do this procedure, you have to achieve a leak at the end of the procedure, or at least in the months that follow-up, that is mild or less. In our series, we showed that those patients that had that, they were independently associated with less deaths and less major adverse cardiovascular events. It's a very clear dichotomy between those groups.     Of course there's all sorts of reasons why you might be able to achieve a good result in a patient, but we know that if you can do it, those patients will be very much better than the others. In our paper we achieved that in around 75% of patients and they did much better than the others. That is a principle finding. There were another of other factors that were associated independently with death and those also included NYHA classification at follow up, but also creatinine baseline. As I've already eluded to, this is a high-risk chord of patients and there are conventional risk factors that will pre-dispose whether someone's going to do well or not. That's what came out in the multi-variable analysis.   Dr. Lam: Very important clinically. Take home message from your point?   Dr. Kumbhani: I think one of the interesting findings was that only 16% of these PVLs were closed for hemolysis. The vast majority of them were done for symptomatic causes. That probably speaks to the dictum that it's the smaller PVLs that cause hemolysis. I don't know if you have a handle, based on your experience, on that?   Dr. Calvert: When we designed the series, a number of years ago ... When you design a registry you look at the things you're going to collect. Then when you've written the paper you think, "I just wish I had collected some more data." That's one of those things we really wish we looked ... It's fascinating. We do this procedure together and one of the things we're terrified about is taking a big leak, getting rid of heart failure and creating hemolysis.   Dr. Kumbhani: Exactly.   Dr. Calvert: We all have had personal experiences of that happening.   Dr. Kumbhani: Yes.   Dr. Calvert: The data we collected, collected patients who had new hemolysis, requiring transfusion. Therefore, all I can tell you from our series is, that was really quite a small ... It was only 2 or 3% of people who had new hemolysis.   Dr. Kumbhani: After the closure?   Dr. Calvert: After the closure. Of course, about 16 or 17% had hemolysis going into it. It doesn't really tell us any information about what happened to those, unfortunately.   Dr. Kumbhani: One other interesting thing that I wanted to point out. If you look at the PCIs registry, all of, there are about 120 hospitals in it. Is that correct?   Dr. Calvert: That's approximately correct, yes.   Dr. Kumbhani: You had 20 centers that were doing this?   Dr. Calvert: Yes.   Dr. Kumbhani: 1 in 6 is doing these in a competent fashion, the PVL closures. I think, as you pointed out, the series are usually single institutions that really specialize in this in the U. S. I think the experience may be a little more consolidated. If you want to just comment on that finding alone?     The second thing is, is there something different about the intervention training procedure in the U.K. that allows for more interventionists to be comfortable doing this?   Dr. Calvert: I think that's a really great question. I think there's a little to pick apart behind that. I think the first thing to say is that, although there were 20 centers that contributed cases, some of those centers would have definitely had proctors come in to do the cases. This is the entire learning curve. This is every case that has contributed in the U.K. It's watching our learning curve and the lot. There will be a number of centers that have been heavily proctored coming in.     One thing that's really nice about the U.K., it's a small country. Particularly in this structural community, most people know each other. If you've got a problem, you ring up your friend down the road and say, "You've done a few of these, come and give us a hand." We get that and I do that too, so that's great.     I think the second thing to say, and I think it's important to say this, our cousins in America are fantastic at doing this procedure. I think they have to be because although the devices are malleable, and they will squash because as we both know, it doesn't matter what the device looks like at the end provided it plugs the hole and is not interfering with the leaflets and it's not falling out. That's fine. I do believe that the oblong devices are more likely to get a good closure. I think therefore, you're less likely to be having to put in 2 or 3 devices in the same sitting. I think that's technically demanding for ... I think it probably is a little more straight forward with the oblong devices.     I think it is important to say for the record, that there's nothing in this paper that is scientifically proven the oblong devices are better. They trend in their right but, it is a fact of the series of oblong devices. Once they're available, it was 72% and for the total it's about 2/3. It's not a scientific comparison but, we've got these good results with these devices.   Dr. Kumbhani: It would not be a fair comparison but in your database, are you able to do some kind of propensity analysis looking at the oblong versus the other devices? Comparing ventricle leak for example or hemolysis?   Dr. Calvert: We don't have enough breakdown data on hemolysis unfortunately. I think I just need to be careful what I say because a lot of the authors came up with hypotheses about things. I looked at the data and I think when we subgroup too much, it became too small to read to give any careful answers.   Dr. Kumbhani: I see.   Dr. Calvert: I think what would be really fascinating, is when we pool data with other countries because I know there are other countries that are looking at this as well. We might get more information, but that's something we have on the horizon so what this space.   Dr. Kumbhani: That's good.   Dr. Lam: That is fantastic. Thank you Patrick. Thank you Darrin. Seriously, I'm floored. I learned so much from this and I really enjoyed this conversation.     Thank you very much, and to the listeners out there, don't forget you've been listening to Circulation on the Run. Join us next week for more highlights and features.    

Dharam Agar Hai Zinda Rakhna Insaan Banana Parega: January 2013 Episode of Voice Divine -The Internet Radio by Mukta Alagh Ji; Rakesh Mutreja Ji