Podcast appearances and mentions of Paul Welsh

Play Episode Listen Later Aug 30, 2021 26:53

This week's episode features special Guest Host Victoria Delgado, as she interviews author Qiang Zhang and Greg (who was the editorialist and handling editor) as they discuss the article "Towards Replacing Late Gadolinium Enhancement with Artificial Intelligence Virtual Native Enhancement for Gadolinium-Free Cardiovascular Magnetic Resonance Tissue Characterization in Hypertrophic Cardiomyopathy." 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 cohost. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. And Carolyn, this week's feature actually is a magnetic resonance imaging paper, which you know, of course, I'm very fond of. And these authors have come up with a new methodology to get information equivalent to a late gadolinium-enhanced exam without administering gadolinium. But before we get to that feature discussion, how about we start in with some of the other articles in this issue? Dr. Carolyn Lam: Yep. Dr. Greg Hundley: Well, how about if I go first? So Carolyn, the first paper I'm going to discuss is from Dr. Paul Welsh from the University of Glasgow, and it pertains to abdominal aortic aneurysms, which you know can occur in patients who are ineligible for routine ultrasound screening. A simple abdominal aortic aneurysm risk score was derived and compared to current guidelines used for ultrasound screening of abdominal aortic aneurysms. Dr. Greg Hundley: And so, this study comes to us from the UK Biobank, and they examined participants without previous, and let's just abbreviate this as AAA or AAA. So without previous AAA, we're split into a derivation cohort of 401,820 individuals, and a validation cohort of 83,000 individuals. An incident AAA was defined as a first hospital, inpatient diagnosis of AAA, death from AAA, or a AAA-related surgical procedure. And, of course, they used multivariable Cox models to develop the derivation cohort, and then apply that to the validation cohort. Dr. Carolyn Lam: Wow, Greg, that is a large number of people, the power of the UK Biobank, huh? So, what did they find? Dr. Greg Hundley: Right. So, Carolyn, components of the AAA risk score were age, stratified by smoking status, weight, stratified by smoking status, any hypertensive and cholesterol-lowering medication use, height, diastolic blood pressure, baseline cardiovascular disease, and then diabetes. Dr. Greg Hundley: So, Carolyn, in the validation cohort, over 10 years of follow-up, the C index, for the model for the USPSTF guidelines, was 0.705, whereas, the C index of the risk score as a continuous variable was 0.856. And in the validation cohort, the USPSTF model yielded a sensitivity of 63%, and a specificity of 71%. Dr. Carolyn Lam: Okay, Greg, but what's a take-home message? Dr. Greg Hundley: Right, Carolyn. So the take-home message is that in an asymptomatic general population, a risk score based on patient age, height, weight, and a medical history may improve identification of asymptomatic patients at risk for clinical events from AAA. And also, these results highlight that further development and validation of risk scores to detect asymptomatic AAA are needed. Dr. Carolyn Lam: Wow, and that was a great summary with a lot more data in the article, huh? Let's refer the readers to it. But for my paper, it highlights the key role of histidine triad nucleotide-binding protein 1, or HINT 1, in the pathogenesis of cardiac hypertrophy. Dr. Greg Hundley: Wow. Carolyn, so tell me a little bit more about HINT 1. Dr. Carolyn Lam: I thought you may ask. HINT 1 is a highly-conserved 14 kilodalton protein that belongs to the histidine triad super family. It was previously shown to play a role in diverse neuropsychiatric diseases. Loss of HINT 1 increased susceptibility to carcinogenesis in mice, suggesting, as well, a tumor suppressor role. So recently, HINT 1 has emerged as a tumor suppressor with multiple molecular mechanisms, involving regulation of apoptosis, gene transcription, and cell cycle control. Dr. Carolyn Lam: Now, with that as a background, today's paper from co-corresponding authors Drs. Ji, Xie and Han, from Nanjing Medical University, used animal models and cell models of hypertrophic growth, and found that HINT 1 deficiency aggravated overload-induced cardiac hypertrophy and fibrosis and deteriorated cardiac dysfunction in mice, whereas, cardiac-specific HINT 1 over-expression attenuated cardiac hypertrophy, and rescued cardiac dysfunction. Dr. Carolyn Lam: Furthermore, the more the authors uncovered Homeobox A5, or Hox A5, as a HINT 1 target gene, which contributed to hypertrophy through activating the TGF beta signal pathway. Combined, these findings demonstrate HINT 1 may be a prognostic biomarker, and this may establish a foundation for future investigation of its potential as a therapeutic target for cardiac hypertrophy and heart failure. Greg Hundley: Great, Carolyn. So, we get a hint for future cardiac hypertrophy. Dr. Carolyn Lam: Hahaha. Dr. Greg Hundley: Couldn't resist. Dr. Carolyn Lam: Bravo. Dr. Greg Hundley: Couldn't resist. So, Carolyn, my next paper comes to us from Dr. Mark Gladwin from the University of Pittsburgh. And, as you know, many patients with one of your faves, heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension. Now, increases in pulmonary vascular resistance, in patients with HFpEF portend a poor prognosis. This phenotype is referred to as combined pre- and post-capillary pulmonary hypertension. Dr. Greg Hundley: And therapeutic trials of exercise-induced pulmonary hypertension, and pre- and post-capillary pulmonary hypertension, have been disappointing, suggesting the need for strategies that target upstream mechanisms of the disease. And so, this work reports novel rat exercise-induced pulmonary hypertension models and mechanisms of pulmonary vascular dysfunction, centered around the transcriptional repression of the soluble guanylate cyclase enzyme in pulmonary artery smooth muscle cells. Dr. Carolyn Lam: Ooh, so much of this is of interest to me, from HFpEF to soluble guanylate cyclase. Ah, all right, so what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So, in the HFpEF and in the pre- and post-capillary pulmonary hypertension models, metabolic syndrome contributed to pulmonary vascular dysfunction and exercise-induced pulmonary hypertension through enhanced reactive oxygen species and MIR193B expression, which downregulates NFYA-dependent soluble guanylate cyclase beta-1 expression, and adenovirus mediated NFYA over-expression and SGLT-2 inhibition restored NFYA soluble guanylate cyclase beta-1 cyclic GMP signaling, and ameliorated exercise-induced pulmonary hypertension. Dr. Greg Hundley: So Carolyn, after all of that, these results uncover a molecular explanation for the unsolved clinical associations linking metabolic syndrome with exercise-induced pulmonary hypertension in patients with pre- and post-capillary pulmonary hypertension, as well as HFpEF. Dr. Carolyn Lam: Wow. That is super, Greg. Thanks. Now, other articles in today's issue include a research letter by Dr. Schunkert on identification of a functional PDE5A variant at the chromosome 4q27 coronary artery disease locus in an extended myocardial infarction family. Dr. Carolyn Lam: There is a policy front paper by Dr. Lackey on applying decision analysis to inform FDA's benefit risk assessment of ticagrelor for primary prevention of myocardial infarction or stroke, based on the THEMIS trial. There's an exchange of letters between Drs. Olson and Reiffel regarding the article emulating randomized controlled trials with non-randomized real-world evidence studies, the first results of the RCT Duplicate Initiative. Dr. Greg Hundley: Great. Carolyn. Well, I've got two other papers. There's an ECG challenge from Professor Macherey entitled, Wide QRS complex bradycardia in a hemodynamically unstable young woman. And then, finally, one of our nice perspective pieces from Dr. Armstrong entitled, Extending the product label for ticagrelor: Looking under the FDA hood. Well, Carolyn, now we're going to learn a little bit more about that non-contrast method of MRI to get, maybe, the equivalent to late gadolinium enhancement in patients with hypertrophic cardiomyopathy. Dr. Carolyn Lam: And all by AI. Very, very cool. All right, let's go. Dr. Victoria Delgado: Hello, I'm Victoria Delgado, associate editor of Circulation, and working at the University Medical Center, and I have the privilege to welcome Dr. Zhang from the University of Oxford, division of cardiovascular medicine, and first author of the article published in Circulation, which presents a new technology that has the potential to change our clinical practice, and how do we assess myocardial tissue characteristics, particularly fibrosis with cardiac magnetic resonance. Dr. Victoria Delgado: With us, we have also Dr. Greg Hundley from VCU Pauley Heart Center, associate editor of Circulation, and host of Circulation on the Run and editorialist of this article. And Greg has handled this article in the review process and guided Dr. Zhang and coworkers to finally get a very impactful, in my opinion, and novel paper that has the potential to change clinical practice. He will help us to put in perspective the main message of this article. But first, Dr. Zhang, why don't you tell us briefly, what is this new technology for myocardial tissue characterization with cardiovascular magnetic resonance, and why did you develop it? Dr. Qiang Zhang: Well, first, I want to say thank you very much for the invitation. Well, as we know, CMR late-gadolinium enhancement, or LGE, has been the imaging gold standard for micro tissue catheterization. However, LGE requires the injection of a contrast agent, which prolongs the scan, increase the cost, and is cautioned in some patient groups. It is therefore desirable to develop a contrast-free technique to replace LGE. A native or pre-contrast CMR such as cine imaging, T1-mapping and the T2-mapping are alternative means for myocardial tissue characterization without the need for contrast. Dr. Qiang Zhang: And notably, T1-mapping can detect a wider range of pathology, but its clinical application is hindered by confounding factors and a lack of clear interpretation. So we thought that since MRI is inherently multimodal and multiparametric, with different modalities reflecting complimentary information about micro tissue, therefore can we use the ones of an AI method to combine the enhanced pre-contrast and modalities to produce a virtual LGE image without the need for contrast, and this leads to our concept of CMR virtual native enhancement. Dr. Victoria Delgado: Excellent. And in which population did you evaluate this technology? Why did you choose? So, can you tell us a little bit the characteristics of the population where you choose to assess the performance of this new technology? Dr. Qiang Zhang: Yes, so we validated this concept first on the hypertrophic cardiomyopathy patients using the image data from HCMR study, which is a larger multinational study. We trained the new network models on about 2,700 images, and then we tested independently on 124 patient materials. Dr. Victoria Delgado: And what were the results? Can you summarize them for us to understand what you found, how you evaluated the performance of this new technology compared to classical late gadolinium enhancement? Dr. Qiang Zhang: Yeah. So, we found that first, the VNE image had significantly better image quality than the traditional LGE, and the secondly, the VNE revealed characteristic HCM lesions in hypertrophic segment and added the anterior and the inferior right ventricular insertion point, and those VNE lesions were in high visual spatial agreement with the lesions detected by LGE. And thirdly, VNE correlated strongly with LGE in quantifying hyperintensity, micro lesions, but also more subtle intermediate-intensity lesions as often observed in the HCM patients. Dr. Victoria Delgado: Exciting. And now I would like to turn to Greg. You are a renowned expert on CMR. What did this article attract you? What were the main findings that you found interesting in this article? Dr. Greg Hundley: Yes. Thank you so much, Victoria. And just first, before I get started, I wanted to thank Zhang for sending us this work, and his entire team really spanning several institutions around the globe. Victoria, I want to thank you for leading this discussion. And Victoria, we work as a team looking at imaging, and what's very impressive is this caught multiple of us on the imaging team, but also the editorial board. So want to thank you Victoria. And then, finally, I want to thank Dr. Charlotte Manisty and Jennifer Jordan who helped with the editorial. Dr. Greg Hundley: So, just to take a little bit of a step back in the year 2000, Dr. Ray Kim, Dr. Bob Bono, Dr. Bob Judd at Northwestern University, in Chicago, administered gadolinium contrast. It's an extra cellular agent and they were examining myocardial perfusion, and then they noticed if they took images 10 or so minutes after that administration, they appreciated this late enhancement of the myocardial tissue that was associated with two things, one myocardial injury, and then, also, scar formation. Dr. Greg Hundley: And for the last 21 years, that technique has been very valuable in assessing infarct size in those with ischemic cardiomyopathy, and then also recognizing extracellular fibrosis or forms of myocardial injury in a variety of non-ischemic cardiomyopathy processes. And one of those is hypertrophic cardiomyopathy. And so, Zhang and his group have been working on a technique that did not utilize gadolinium anymore. And they based this on, really, had two important features. Dr. Greg Hundley: One is, some examination of the T1 relaxation that's available when you acquire magnetic resonance images, and then also applying artificial intelligence to analysis of these images. Those two factors allowed this investigative team to produce images that are very similar to what we appreciate with gadolinium enhancement in patients with hypertrophic cardiomyopathy. And why is that significant? So administration of gadolinium, we think about two things, again, that are an issue with that. Dr. Greg Hundley: Well, one, we've got to give the contrast agent, and some patients are not well-suited. If you have renal dysfunction, you can develop nephrogenic systemic fibrosis, a scleroderma-like syndrome when the gadolinium is not cleared, and it's stays in your body a long time. The other thing we tend to worry about much more recently was accumulation of gadolinium in the brain stem. We don't know that that has an adverse effect, but we're certainly aware of it. Dr. Greg Hundley: And finally, I guess there is a third point. There are a few patients, one in 20 to 40,000 that have allergic reactions. So, for all those patients that really can't get gadolinium, this is another potential opportunity moving forward. The second point is time. So during an MRI scan time, or process, we administer the gadolinium. And remember what I said, we've got to wait about 10 minutes to then collect these images. Well, if you can have a technique where you don't have to administer gadolinium, you get the same administration and you don't have to wait that 10 minutes, we might be able to save a large amount of time. And you say, well, 10 minutes, what does that mean? Dr. Greg Hundley: But if you're doing many patients during the day, that really could equate to a big time-savings. So what attracted us to this article? A technical innovation that perhaps may obviate the need for the administration of gadolinium in many cases, and here in these patients with hypertrophic cardiomyopathy, I think the images were quite stunning in that they appreciated the extent of the fibrosis and scar in patients with hypertrophic cardiomyopathy to the same degree, and maybe even with higher image quality than we had in the gadolinium-enhanced comparitors. Dr. Victoria Delgado: Yeah. I agree with all those comments, indeed. For these 20 years, there have been other developments, in terms of assessing diffuse fibrosis with T1-mapping techniques after administration of gadolinium, but also before administration of gadolinium. And this technology Dr. Zhang and co-workers have shown actually reduces the time of acquisition because you only need 15 minutes to acquire the cine images and the T1 images. And the analysis is not very long in terms of post-processing, because it's also very short. As seen the paper was indicated. Dr. Victoria Delgado: And as you said, the administration of gadolinium enhancement is not free of potential risks. And in these patients, for example, we have hypertrophic cardiomyopathy that can undergo repetitive evaluations during follow-up. The use of this imaging technique can help to reduce the exposure to gadolinium enhancement. Dr. Victoria Delgado: Now, the question for you, Qiang, will be, what are the next steps for you and your team to further develop this technique, to further convince the community to implement this technique in clinical practice, and that can have an impact in our management of these patients with hypertrophic cardiomyopathy, or with other patients on whom we also evaluate the presence of myocardial fibrosis? Dr. Qiang Zhang: Thank you, Victoria. And thank you Greg, for the very insightful comments. So we think that the immediate future work would be to validate the VNE HCMR study clinical outcomes as a potential new contrast-free biomarker for HCM patients. And in the meantime, we are working on extending the method to other pathologies, particularly myocardial infarction, for viability assessment. Dr. Qiang Zhang: And we also think that the concept of AI virtual contrast agent maybe apply it to other post-contrast images, such as early gadolinium enhancement and extracellular volume refraction mapping, or even, maybe, first perfusion. And also in collaboration with MR vendors, we plan to implement VNE as inline sequence on the scanner to display lesions immediately after the pre-contrast cine and the T1-mapping acquisitions. Dr. Victoria Delgado: Very interesting. And Greg, another group of patients, for example, that I'm thinking of where this technology can be very helpful, and you have expertise on this, are patients undergoing treatment with chemotherapy, what we need to address, for example, or to evaluate the presence of cardiac toxicity. Would you see in this population the value of this technique, or how do you see the future of these technique in clinical practice? Dr. Greg Hundley: Yeah. Great questions, Victoria. I think probably five things and many of those Qiang has already just brought up. One, with the current study, it's going to be great to follow these patients over time and look at the outcomes. What did amount, presence, location of the findings with this new technique, how did they equate to outcomes in patients with hypertrophic cardiomyopathy? So we're going to anxiously await that. Dr. Greg Hundley: I think once we move out of the current study, thinking about other vendors, using this and acquiring images from General Electric and Phillips, and multiple vendors around the world and multiple field strengths, how do we going to understand the findings there? I think another particular issue will be different diseases as Qiang ha said, ischemic cardiomyopathy. Well, what about amyloid? Victoria, you've mentioned using the other possibility here is, can this technique help us produce something similar to extracellular volume fraction measures? And could that be used to identify interstitial disease processes? Dr. Greg Hundley: And, for example, as you mentioned, the fibrosis that's associated with the administration of certain chemotherapeutic agents or radiation therapy. I think another thing is, Qiang, can we go back and use retrospectively-collected data? Can your technique be modified so that many of the studies that have been performed in the past, large population studies, like Mesa or a Framingham or Jackson heart study, and could we use that to develop forecasting and algorithms moving forward? Dr. Greg Hundley: And then, lastly, I think as you mentioned, the artificial intelligence component of what you've described and how's that can compare when Victoria and I look at the images, and could we get into combining reads from one institution, reads from another, reads from another, tracking outcomes? And so, when a patient comes in and has a study performed, your artificial intelligence, not only does it read that study and highlights the increased signal in the myocardium, but then goes and looks at outcomes across multiple sites, and what would that mean for a given patient with a different condition? So, oh my goodness, the horizon is just so expansive here. The future is very bright. And just to congratulate you on, I really think this could be another landmark technical innovation, so fantastic work. Dr. Victoria Delgado: Indeed. Thank you very much, Greg, for all these insightful comments and these perspectives that we have in the future, particularly with the use of this technique in retrospective studies in large cities, that where we can develop these algorithms. And I would like also to thank Qiang for submitting your article to Circulation, for giving us the opportunity to present this new technology and make this article, like the landmark article, where there will be many other articles to follow. We hope that you also choose us. Dr. Victoria Delgado: But with this, I would like to thank both of you, Greg and Qiang, for the excellent discussion that we have had in this new technology, based on artificial intelligence, that can identify myocardial fibrosis without the use of gadolinium enhancement, that maybe by now will be obsolete in the future, and that can impact on how we do our clinical practice. Many thanks to all of you and happy to discuss in the future other articles. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, I want to thank our speakers, and then also, wish everyone a great week. And we will catch you next week On the Run. 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.

Circulation August 24, 2021 Issue

director asda harrogate nick hancock paul welsh

Play Episode Listen Later Aug 23, 2021 25:26

This week's episode features special Guest Host Victoria Delgado, as she interviews author Qiang Zhang and Greg (who was the editorialist and handling editor) as they discuss the article "Towards Replacing Late Gadolinium Enhancement with Artificial Intelligence Virtual Native Enhancement for Gadolinium-Free Cardiovascular Magnetic Resonance Tissue Characterization in Hypertrophic Cardiomyopathy." 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 cohost. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. And Carolyn, this week's feature actually is a magnetic resonance imaging paper, which you know, of course, I'm very fond of. And these authors have come up with a new methodology to get information equivalent to a late gadolinium-enhanced exam without administering gadolinium. But before we get to that feature discussion, how about we start in with some of the other articles in this issue? Dr. Carolyn Lam: Yep. Dr. Greg Hundley: Well, how about if I go first? So Carolyn, the first paper I'm going to discuss is from Dr. Paul Welsh from the University of Glasgow, and it pertains to abdominal aortic aneurysms, which you know can occur in patients who are ineligible for routine ultrasound screening. A simple abdominal aortic aneurysm risk score was derived and compared to current guidelines used for ultrasound screening of abdominal aortic aneurysms. Dr. Greg Hundley: And so, this study comes to us from the UK Biobank, and they examined participants without previous, and let's just abbreviate this as AAA or AAA. So without previous AAA, we're split into a derivation cohort of 401,820 individuals, and a validation cohort of 83,000 individuals. An incident AAA was defined as a first hospital, inpatient diagnosis of AAA, death from AAA, or a AAA-related surgical procedure. And, of course, they used multivariable Cox models to develop the derivation cohort, and then apply that to the validation cohort. Dr. Carolyn Lam: Wow, Greg, that is a large number of people, the power of the UK Biobank, huh? So, what did they find? Dr. Greg Hundley: Right. So, Carolyn, components of the AAA risk score were age, stratified by smoking status, weight, stratified by smoking status, any hypertensive and cholesterol-lowering medication use, height, diastolic blood pressure, baseline cardiovascular disease, and then diabetes. Dr. Greg Hundley: So, Carolyn, in the validation cohort, over 10 years of follow-up, the C index, for the model for the USPSTF guidelines, was 0.705, whereas, the C index of the risk score as a continuous variable was 0.856. And in the validation cohort, the USPSTF model yielded a sensitivity of 63%, and a specificity of 71%. Dr. Carolyn Lam: Okay, Greg, but what's a take-home message? Dr. Greg Hundley: Right, Carolyn. So the take-home message is that in an asymptomatic general population, a risk score based on patient age, height, weight, and a medical history may improve identification of asymptomatic patients at risk for clinical events from AAA. And also, these results highlight that further development and validation of risk scores to detect asymptomatic AAA are needed. Dr. Carolyn Lam: Wow, and that was a great summary with a lot more data in the article, huh? Let's refer the readers to it. But for my paper, it highlights the key role of histidine triad nucleotide-binding protein 1, or HINT 1, in the pathogenesis of cardiac hypertrophy. Dr. Greg Hundley: Wow. Carolyn, so tell me a little bit more about HINT 1. Dr. Carolyn Lam: I thought you may ask. HINT 1 is a highly-conserved 14 kilodalton protein that belongs to the histidine triad super family. It was previously shown to play a role in diverse neuropsychiatric diseases. Loss of HINT 1 increased susceptibility to carcinogenesis in mice, suggesting, as well, a tumor suppressor role. So recently, HINT 1 has emerged as a tumor suppressor with multiple molecular mechanisms, involving regulation of apoptosis, gene transcription, and cell cycle control. Dr. Carolyn Lam: Now, with that as a background, today's paper from co-corresponding authors Drs. Ji, Xie and Han, from Nanjing Medical University, used animal models and cell models of hypertrophic growth, and found that HINT 1 deficiency aggravated overload-induced cardiac hypertrophy and fibrosis and deteriorated cardiac dysfunction in mice, whereas, cardiac-specific HINT 1 over-expression attenuated cardiac hypertrophy, and rescued cardiac dysfunction. Dr. Carolyn Lam: Furthermore, the more the authors uncovered Homeobox A5, or Hox A5, as a HINT 1 target gene, which contributed to hypertrophy through activating the TGF beta signal pathway. Combined, these findings demonstrate HINT 1 may be a prognostic biomarker, and this may establish a foundation for future investigation of its potential as a therapeutic target for cardiac hypertrophy and heart failure. Greg Hundley: Great, Carolyn. So, we get a hint for future cardiac hypertrophy. Dr. Carolyn Lam: Hahaha. Dr. Greg Hundley: Couldn't resist. Dr. Carolyn Lam: Bravo. Dr. Greg Hundley: Couldn't resist. So, Carolyn, my next paper comes to us from Dr. Mark Gladwin from the University of Pittsburgh. And, as you know, many patients with one of your faves, heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension. Now, increases in pulmonary vascular resistance, in patients with HFpEF portend a poor prognosis. This phenotype is referred to as combined pre- and post-capillary pulmonary hypertension. Dr. Greg Hundley: And therapeutic trials of exercise-induced pulmonary hypertension, and pre- and post-capillary pulmonary hypertension, have been disappointing, suggesting the need for strategies that target upstream mechanisms of the disease. And so, this work reports novel rat exercise-induced pulmonary hypertension models and mechanisms of pulmonary vascular dysfunction, centered around the transcriptional repression of the soluble guanylate cyclase enzyme in pulmonary artery smooth muscle cells. Dr. Carolyn Lam: Ooh, so much of this is of interest to me, from HFpEF to soluble guanylate cyclase. Ah, all right, so what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So, in the HFpEF and in the pre- and post-capillary pulmonary hypertension models, metabolic syndrome contributed to pulmonary vascular dysfunction and exercise-induced pulmonary hypertension through enhanced reactive oxygen species and MIR193B expression, which downregulates NFYA-dependent soluble guanylate cyclase beta-1 expression, and adenovirus mediated NFYA over-expression and SGLT-2 inhibition restored NFYA soluble guanylate cyclase beta-1 cyclic GMP signaling, and ameliorated exercise-induced pulmonary hypertension. Dr. Greg Hundley: So Carolyn, after all of that, these results uncover a molecular explanation for the unsolved clinical associations linking metabolic syndrome with exercise-induced pulmonary hypertension in patients with pre- and post-capillary pulmonary hypertension, as well as HFpEF. Dr. Carolyn Lam: Wow. That is super, Greg. Thanks. Now, other articles in today's issue include a research letter by Dr. Schunkert on identification of a functional PDE5A variant at the chromosome 4q27 coronary artery disease locus in an extended myocardial infarction family. Dr. Carolyn Lam: There is a policy front paper by Dr. Lackey on applying decision analysis to inform FDA's benefit risk assessment of ticagrelor for primary prevention of myocardial infarction or stroke, based on the THEMIS trial. There's an exchange of letters between Drs. Olson and Reiffel regarding the article emulating randomized controlled trials with non-randomized real-world evidence studies, the first results of the RCT Duplicate Initiative. Dr. Greg Hundley: Great. Carolyn. Well, I've got two other papers. There's an ECG challenge from Professor Macherey entitled, Wide QRS complex bradycardia in a hemodynamically unstable young woman. And then, finally, one of our nice perspective pieces from Dr. Armstrong entitled, Extending the product label for ticagrelor: Looking under the FDA hood. Well, Carolyn, now we're going to learn a little bit more about that non-contrast method of MRI to get, maybe, the equivalent to late gadolinium enhancement in patients with hypertrophic cardiomyopathy. Dr. Carolyn Lam: And all by AI. Very, very cool. All right, let's go. Dr. Victoria Delgado: Hello, I'm Victoria Delgado, associate editor of Circulation, and working at the University Medical Center, and I have the privilege to welcome Dr. Zhang from the University of Oxford, division of cardiovascular medicine, and first author of the article published in Circulation, which presents a new technology that has the potential to change our clinical practice, and how do we assess myocardial tissue characteristics, particularly fibrosis with cardiac magnetic resonance. Dr. Victoria Delgado: With us, we have also Dr. Greg Hundley from VCU Pauley Heart Center, associate editor of Circulation, and host of Circulation on the Run and editorialist of this article. And Greg has handled this article in the review process and guided Dr. Zhang and coworkers to finally get a very impactful, in my opinion, and novel paper that has the potential to change clinical practice. He will help us to put in perspective the main message of this article. But first, Dr. Zhang, why don't you tell us briefly, what is this new technology for myocardial tissue characterization with cardiovascular magnetic resonance, and why did you develop it? Dr. Qiang Zhang: Well, first, I want to say thank you very much for the invitation. Well, as we know, CMR late-gadolinium enhancement, or LGE, has been the imaging gold standard for micro tissue catheterization. However, LGE requires the injection of a contrast agent, which prolongs the scan, increase the cost, and is cautioned in some patient groups. It is therefore desirable to develop a contrast-free technique to replace LGE. A native or pre-contrast CMR such as cine imaging, T1-mapping and the T2-mapping are alternative means for myocardial tissue characterization without the need for contrast. Dr. Qiang Zhang: And notably, T1-mapping can detect a wider range of pathology, but its clinical application is hindered by confounding factors and a lack of clear interpretation. So we thought that since MRI is inherently multimodal and multiparametric, with different modalities reflecting complimentary information about micro tissue, therefore can we use the ones of an AI method to combine the enhanced pre-contrast and modalities to produce a virtual LGE image without the need for contrast, and this leads to our concept of CMR virtual native enhancement. Dr. Victoria Delgado: Excellent. And in which population did you evaluate this technology? Why did you choose? So, can you tell us a little bit the characteristics of the population where you choose to assess the performance of this new technology? Dr. Qiang Zhang: Yes, so we validated this concept first on the hypertrophic cardiomyopathy patients using the image data from HCMR study, which is a larger multinational study. We trained the new network models on about 2,700 images, and then we tested independently on 124 patient materials. Dr. Victoria Delgado: And what were the results? Can you summarize them for us to understand what you found, how you evaluated the performance of this new technology compared to classical late gadolinium enhancement? Dr. Qiang Zhang: Yeah. So, we found that first, the VNE image had significantly better image quality than the traditional LGE, and the secondly, the VNE revealed characteristic HCM lesions in hypertrophic segment and added the anterior and the inferior right ventricular insertion point, and those VNE lesions were in high visual spatial agreement with the lesions detected by LGE. And thirdly, VNE correlated strongly with LGE in quantifying hyperintensity, micro lesions, but also more subtle intermediate-intensity lesions as often observed in the HCM patients. Dr. Victoria Delgado: Exciting. And now I would like to turn to Greg. You are a renowned expert on CMR. What did this article attract you? What were the main findings that you found interesting in this article? Dr. Greg Hundley: Yes. Thank you so much, Victoria. And just first, before I get started, I wanted to thank Zhang for sending us this work, and his entire team really spanning several institutions around the globe. Victoria, I want to thank you for leading this discussion. And Victoria, we work as a team looking at imaging, and what's very impressive is this caught multiple of us on the imaging team, but also the editorial board. So want to thank you Victoria. And then, finally, I want to thank Dr. Charlotte Manisty and Jennifer Jordan who helped with the editorial. Dr. Greg Hundley: So, just to take a little bit of a step back in the year 2000, Dr. Ray Kim, Dr. Bob Bono, Dr. Bob Judd at Northwestern University, in Chicago, administered gadolinium contrast. It's an extra cellular agent and they were examining myocardial perfusion, and then they noticed if they took images 10 or so minutes after that administration, they appreciated this late enhancement of the myocardial tissue that was associated with two things, one myocardial injury, and then, also, scar formation. Dr. Greg Hundley: And for the last 21 years, that technique has been very valuable in assessing infarct size in those with ischemic cardiomyopathy, and then also recognizing extracellular fibrosis or forms of myocardial injury in a variety of non-ischemic cardiomyopathy processes. And one of those is hypertrophic cardiomyopathy. And so, Zhang and his group have been working on a technique that did not utilize gadolinium anymore. And they based this on, really, had two important features. Dr. Greg Hundley: One is, some examination of the T1 relaxation that's available when you acquire magnetic resonance images, and then also applying artificial intelligence to analysis of these images. Those two factors allowed this investigative team to produce images that are very similar to what we appreciate with gadolinium enhancement in patients with hypertrophic cardiomyopathy. And why is that significant? So administration of gadolinium, we think about two things, again, that are an issue with that. Dr. Greg Hundley: Well, one, we've got to give the contrast agent, and some patients are not well-suited. If you have renal dysfunction, you can develop nephrogenic systemic fibrosis, a scleroderma-like syndrome when the gadolinium is not cleared, and it's stays in your body a long time. The other thing we tend to worry about much more recently was accumulation of gadolinium in the brain stem. We don't know that that has an adverse effect, but we're certainly aware of it. Dr. Greg Hundley: And finally, I guess there is a third point. There are a few patients, one in 20 to 40,000 that have allergic reactions. So, for all those patients that really can't get gadolinium, this is another potential opportunity moving forward. The second point is time. So during an MRI scan time, or process, we administer the gadolinium. And remember what I said, we've got to wait about 10 minutes to then collect these images. Well, if you can have a technique where you don't have to administer gadolinium, you get the same administration and you don't have to wait that 10 minutes, we might be able to save a large amount of time. And you say, well, 10 minutes, what does that mean? Dr. Greg Hundley: But if you're doing many patients during the day, that really could equate to a big time-savings. So what attracted us to this article? A technical innovation that perhaps may obviate the need for the administration of gadolinium in many cases, and here in these patients with hypertrophic cardiomyopathy, I think the images were quite stunning in that they appreciated the extent of the fibrosis and scar in patients with hypertrophic cardiomyopathy to the same degree, and maybe even with higher image quality than we had in the gadolinium-enhanced comparitors. Dr. Victoria Delgado: Yeah. I agree with all those comments, indeed. For these 20 years, there have been other developments, in terms of assessing diffuse fibrosis with T1-mapping techniques after administration of gadolinium, but also before administration of gadolinium. And this technology Dr. Zhang and co-workers have shown actually reduces the time of acquisition because you only need 15 minutes to acquire the cine images and the T1 images. And the analysis is not very long in terms of post-processing, because it's also very short. As seen the paper was indicated. Dr. Victoria Delgado: And as you said, the administration of gadolinium enhancement is not free of potential risks. And in these patients, for example, we have hypertrophic cardiomyopathy that can undergo repetitive evaluations during follow-up. The use of this imaging technique can help to reduce the exposure to gadolinium enhancement. Dr. Victoria Delgado: Now, the question for you, Qiang, will be, what are the next steps for you and your team to further develop this technique, to further convince the community to implement this technique in clinical practice, and that can have an impact in our management of these patients with hypertrophic cardiomyopathy, or with other patients on whom we also evaluate the presence of myocardial fibrosis? Dr. Qiang Zhang: Thank you, Victoria. And thank you Greg, for the very insightful comments. So we think that the immediate future work would be to validate the VNE HCMR study clinical outcomes as a potential new contrast-free biomarker for HCM patients. And in the meantime, we are working on extending the method to other pathologies, particularly myocardial infarction, for viability assessment. Dr. Qiang Zhang: And we also think that the concept of AI virtual contrast agent maybe apply it to other post-contrast images, such as early gadolinium enhancement and extracellular volume refraction mapping, or even, maybe, first perfusion. And also in collaboration with MR vendors, we plan to implement VNE as inline sequence on the scanner to display lesions immediately after the pre-contrast cine and the T1-mapping acquisitions. Dr. Victoria Delgado: Very interesting. And Greg, another group of patients, for example, that I'm thinking of where this technology can be very helpful, and you have expertise on this, are patients undergoing treatment with chemotherapy, what we need to address, for example, or to evaluate the presence of cardiac toxicity. Would you see in this population the value of this technique, or how do you see the future of these technique in clinical practice? Dr. Greg Hundley: Yeah. Great questions, Victoria. I think probably five things and many of those Qiang has already just brought up. One, with the current study, it's going to be great to follow these patients over time and look at the outcomes. What did amount, presence, location of the findings with this new technique, how did they equate to outcomes in patients with hypertrophic cardiomyopathy? So we're going to anxiously await that. Dr. Greg Hundley: I think once we move out of the current study, thinking about other vendors, using this and acquiring images from General Electric and Phillips, and multiple vendors around the world and multiple field strengths, how do we going to understand the findings there? I think another particular issue will be different diseases as Qiang ha said, ischemic cardiomyopathy. Well, what about amyloid? Victoria, you've mentioned using the other possibility here is, can this technique help us produce something similar to extracellular volume fraction measures? And could that be used to identify interstitial disease processes? Dr. Greg Hundley: And, for example, as you mentioned, the fibrosis that's associated with the administration of certain chemotherapeutic agents or radiation therapy. I think another thing is, Qiang, can we go back and use retrospectively-collected data? Can your technique be modified so that many of the studies that have been performed in the past, large population studies, like Mesa or a Framingham or Jackson heart study, and could we use that to develop forecasting and algorithms moving forward? Dr. Greg Hundley: And then, lastly, I think as you mentioned, the artificial intelligence component of what you've described and how's that can compare when Victoria and I look at the images, and could we get into combining reads from one institution, reads from another, reads from another, tracking outcomes? And so, when a patient comes in and has a study performed, your artificial intelligence, not only does it read that study and highlights the increased signal in the myocardium, but then goes and looks at outcomes across multiple sites, and what would that mean for a given patient with a different condition? So, oh my goodness, the horizon is just so expansive here. The future is very bright. And just to congratulate you on, I really think this could be another landmark technical innovation, so fantastic work. Dr. Victoria Delgado: Indeed. Thank you very much, Greg, for all these insightful comments and these perspectives that we have in the future, particularly with the use of this technique in retrospective studies in large cities, that where we can develop these algorithms. And I would like also to thank Qiang for submitting your article to Circulation, for giving us the opportunity to present this new technology and make this article, like the landmark article, where there will be many other articles to follow. We hope that you also choose us. Dr. Victoria Delgado: But with this, I would like to thank both of you, Greg and Qiang, for the excellent discussion that we have had in this new technology, based on artificial intelligence, that can identify myocardial fibrosis without the use of gadolinium enhancement, that maybe by now will be obsolete in the future, and that can impact on how we do our clinical practice. Many thanks to all of you and happy to discuss in the future other articles. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, I want to thank our speakers, and then also, wish everyone a great week. And we will catch you next week On the Run. 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.

Your Harrogate Podcast - Episode 123

Your Harrogate

Play Episode Listen Later May 11, 2021 11:28

Nick Hancock is joined by Kate Rogata, Director of Supporting Older People (SOP) in Harrogate! Kate tells us about the organisation and how they support elderly people through ‘befriending' - particularly during lockdown when friendship has been needed most. Kate also tells us about the group's amazing volunteers and their food scheme in which they've teamed up with Asda, Tech Buyer and Paul Welsh to provide more than 10,000 meals for people struggling to put food on the table during the pandemic.

Cycling - Does the health benefit outweigh the accident risk (in the UK)

The BMJ Podcast

Play Episode Listen Later Mar 12, 2020 22:46

We all know we should be doing more exercise, and one way to do that is by active commuting - journeying to work on foot or by bike. One thing preventing people from taking up cycling is the fear of being involved in road traffic accidents, and that the risk isn't worth the benefit of the extra exercise. It's even more confusing when air pollution has to be taken into account. Joining us to discuss new research into that risk/benefit calculation are Paul Welsh, a Senior Lecturer, and Carlos Celis, a research fellow, both Institute of Cardiovascular & Medical Sciences at the University of Glasgow. Read their open access research - Association of injury related hospital admissions with commuting by bicycle in the UK: prospective population based study https://www.bmj.com/content/368/bmj.m336

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Part 6: From Flatline to Back Nine

Brooklyn Nine-Nine: The Podcast

Play Episode Listen Later Feb 3, 2020 77:42

Brooklyn Nine-Nine: The Podcast’s host Marc Evan Jackson cops a squat with writers Paul Welsh and Madeline Walter, co-creator/executive producer Dan Goor, Joe Lo Truglio (Charles Boyle), Stephanie Beatriz (Rosa Diaz), production coordinator Beatriz Chahin and director of photography Rick Page. They talk about the sixth and most recent season of Brooklyn Nine-Nine - more specifically, the season finale episode, “Suicide Squad”- as well as the series as a whole and its reception and impact on television and pop culture. Be sure to subscribe for more behind-the-scenes stories, performance notes and more! Brooklyn Nine-Nine: The Podcast is a production of NBC Entertainment Podcast Network © 2020

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Episode 120: Paul Welsh

The Need to Fail with Don Fanelli

Play Episode Listen Later Dec 3, 2019 78:42

Paul Welsh (Brooklyn99, Crazy-Ex Girlfriend) was flown out back out to NY after he moved to LA and crushed his Daily Show audition - and didn't get it. We chat about why it took him multiple attempts to get onto a UCB Harold Team, how he dealt with a failed pilot he co-wrote, and how a short film he made, whose script got him his agent, got into zero festivals. CONNECT W/ THE NEED TO FAIL & DON FANELLI ON TWITTER: https://twitter.com/theneedtofailhttps://twitter.com/donfanelli AND PLEASE SUPPORT TN2F ON PATREON FOR BONUS EPS & MORE: https://www.patreon.com/theneedtofail SUBSCRIBE/RATE/REVIEW TN2F on Apple Podcasts, Google Play, Stitcher, Spotify or wherever you get your podcasts. THE NEED TO FAIL IS A FOREVER DOG PODCAST http://foreverdogproductions.com/fdpn/podcasts/the-need-to-fail Learn more about your ad choices. Visit megaphone.fm/adchoices

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The Big Fish Aunty Jack Fish

kayak big fish aunty stinker kingfish kayak fishing paul welsh

Play Episode Listen Later Nov 22, 2019 60:00

Kayak fisher Paul Welsh will join us on The Big Fish to talk about the metre plus Kingfish that have moved into our inshore waters, this one went 1.32m and weighed 17 kilos, they get a lot, lot bigger! When Paul was asked how you deal with a Kingfish that big in a kayak he said, "you hang on and enjoy the ride". Paul calls them Auntie Jack because they can "rip your bloody arms off!"

Sasheer is Unpacking The Peanuts with Paul Welsh & Madeline Walter

Best Friends with Nicole Byer and Sasheer Zamata

Play Episode Listen Later Sep 10, 2019 101:45

After Nicole tries to remember the title of this podcast, she and Sasheer are joined by best friends Paul Welsh & Madeline Walter (Brooklyn Nine-Nine)! Paul talks about people crossing boundaries to touch his thick hair, how he and Madeline met, Madeline’s love of the Minneapolis airport, and disliking Game Of Thrones. Madeline shares about their early days of comedy, how attentive Paul is as a friend, the Peanuts (Pig Pen is NOT thriving), and how she loves the Raleigh-Durham airport. Then, Nicole and Sasheer bring Paul & Madeline together Newlywed Game-style, and get to the bottom of the airport discrepancy, Orange Soda Guy, and how many is too many band-aids. Email or call Nicole & Sasheer with your friendship questions at: nicoleandsasheer@gmail.com (424) 645-7003‬ This episode is sponsored by Weeknight Kitchen with Melissa Clark, MeUndies (www.meundies.com/bestfriends), Parcast (www.parcast.com/Horoscope), and ThirdLove (www.thirdlove.com/bestfriends).

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The Big Fish kayak fishing tiger sharks and big kings

Play Episode Listen Later Sep 6, 2019 60:00

This week on The Big Fish the Morse code of how to fight BIG fish on fly gear. Peter Morse has caught plenty of very big fish on fly gear and shares some hard won ideas on how to land them. Paul Welsh takes us kayak fishing and talks about a very close encounter with a tiger shark and we hear about the epic capture of this lovely kingy.

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Circulation August 13, 2019 Issue

Play Episode Listen Later Aug 12, 2019 23:09

Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your cohosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Greg Hundley, associate editor from the Poly Heart Center at VCU health in Richmond, Virginia. Carolyn, oh, this is going to be an exciting featured article today, and we're going to discuss the combination of agents or their administration et al that are best suited for managing both anticoagulation and antiplatelet therapy and those with coronary disease, peripheral arterial disease and heart failure. And, we'll speak with Dr Kelley Branch from the University of Washington. Dr Carolyn Lam: And me! Dr Greg Hundley: Yes. How am I going to interview you? And, we'll discuss the utility of Rivaroxaban with or without aspirin in patients with heart failure or peripheral arterial disease from the compass trial. Dr Carolyn Lam: Well, I'm not going to let you get there until I tell you about this first basic paper I've chosen because it focuses on the unfolded protein response. Dr Greg Hundley: What's that? Dr Carolyn Lam: Well, Greg, I was really hoping you'd ask. The unfolded protein response is a cellular adaptive process to cope with protein folding stress. Now, approximately 40% of human proteins are predicted to be either transmembrane or secretory. The synthesis, the folding, the cellular transportation and location of these proteins rely on proper functioning of this secretory pathway. Numerous studies have established that the unfolded protein response plays versatile roles during development and under physiologic and pathophysiologic conditions. However, the role of this unfolded protein response in the regulation of cardiomyocyte growth is unclear. Dr Greg Hundley: That's fantastic, Carolyn. I've already learned something here. So, what did this paper show? Dr Carolyn Lam: This is from Dr Wang and colleagues from UT Southwestern, and basically, they use both gain and loss of function approaches to genetically manipulate spliced X-box binding protein one or XBP1, which is the most conserved signaling branch of the unfolded protein response in the heart. In addition, primary cardiomyocyte cultures were employed to address the role of XBP1S in cell growth in a cell autonomous manner. They found that XBP1S expression was reduced in both human and Rhode and cardiac tissues with heart failure deficiency of XBP1S lead to decompensation and exacerbation of heart failure progression under pressure overload. On the other hand, cardiac restricted over expression of XBP1S prevented the development of cardiac dysfunction. Mechanistically, they found that XBP1S stimulated adaptive cardiac growth, your activation of mechanistic target of rapamycin or MTOR signaling which is mediated via the FK-506 binding protein 11, which is a novel transcriptional target of XBP1S. So in conclusion, this study really showed a critical role of the XBP1S FKB or FK-506 binding protein 11 and MTOR axis in coupling the unfolded protein response and cardiac cell growth regulation. Dr Greg Hundley: Boy Carolyn, you explained that so well, and I learned a lot from that. I hope I can do as well with this next article from Professor Johann Backs from the University of Heidelberg. Now paradoxically, some glucose lowering drugs have been shown to worsen heart failure, raising the question of how glucose mediates protective versus detrimental cardiac signaling, and this study from his group focused on one of the class two histone deacetylases or HDAC's namely HDAC-4, which functions as an important epigenetic regulator by responding to upstream stress signals, and linking them to downstream gene regulatory programs involved in among other things, metabolic regulation. Dr Carolyn Lam: Very interesting. So what did they find? Dr Greg Hundley: What they found is that HDAC4 acts as an important maintenance factor of cardiac function in diabetes and O-glycine-N0acetylglucosamine of HDAC4 at searing 642 induces the production of cardio-protective HDAC F-end terminal fragment and attenuates cardio detrimental Cam kinase two mediated phosphorylation of HDAC4 at searing 632. Vice versa, Cam kinase two mediated phosphorylation of HDAC4 at searing 632 attenuates HDAC-4 n terminal production. Thus, these findings lay the ground for the development of novel therapeutic strategies for diabetic patients with heart failure by inhibiting Cam kinase phosphorylation at CIHR 632 or enhancing o-glycine and escalation at searing 642. Dr Carolyn Lam: Fascinating, Greg. Well, my next paper is a subgroup analysis of EUCLID and is the first to assess acute limb ischemia in the context of a large-scale clinical trial studying a primary peripheral artery disease population. Dr Greg Hundley: So Carolyn, reminded us what was the EUCLID trial. Dr Carolyn Lam: Okay, so EUCLID stands for Examining Use of Ticagrelor in Peripheral Artery Disease, and this was a randomized clinical trial that included acute limb ischemia as an adjudicated outcome in a primary peripheral artery disease population randomized to ticagrelor versus clopidogrel. Now in EUCLID ticagrelor was not superior to Clopidogrel for the prevention of cardiovascular events in patients with stable peripheral artery disease. However, a EUCLID subgroup analysis of patients with and without prior limb revascularization demonstrated significantly higher risk for acute limb ischemia hospitalization in patients with prior low extremity revascularization. Dr Greg Hundley: So Carolyn, that's interesting. So, what did they find related in this study that focused on the acute limb ischemia? Dr Carolyn Lam: Right. So, today's paper is from Dr Hess and colleagues at University of Colorado School of Medicine and CPC, clinical research in Aurora, Colorado. And, they found that acute limb ischemia occurred in 1.7% of almost 13,900 randomized patients with a median time to hospitalization for acute limb Ischemia of 320 days after randomization. In this population, prior lower extremity revascularization, atrial fibrillation and lower ankle brachial index identified patients at higher risk for acute limb ischemia. Hospitalization for acute limb ischemia was associated with subsequent cardiovascular and limb ischemic events. So, the take home message is providers should monitor for signs and symptoms of acute limb ischemia in patients with stable symptomatic peripheral artery disease, particularly those with prior lower extremity revascularization, atrial fibrillation, and lower ankle brachial index. Dr Greg Hundley: That's very instructive, Carolyn. Fantastic message. So, I'm going to ask you if you could select one lipid biomarker to forecast future adverse cardiovascular events, which would you select? Total cholesterol, HTLC, non-HTLC, direct and calculated LDLC, APO-A1, or APO-B? Dr Carolyn Lam: Well, I'm traditional. I would have chosen LDL. Dr Greg Hundley: Okay. Well, the authors of this study led by Dr Paul Welsh at the University of Glasgow attempted to answer this question by studying participants from the UK Biobank without baseline cardiovascular disease and not taking statins with relevant lipid measurements. They had 346,686 participants. An incident fatal or nonfatal cardiovascular event occurred in 6,200 participants of which 1,656 were fatal, and they occurred over a median time of 8.9 years. So, the associations of non-fasting lipid measurements, total cholesterol, HDLC, non HDLC, direct and calculated LDLC, APO-a1, and APO-B with cardiovascular disease were compared using Cox models, adjusting for classical risk factors and predictive utility was determined by the C-index and net reclassification index. Also, prediction was tested in 68,649 participants taking a statin with or without baseline cardiovascular disease, and that group experienced 3,515 cardiovascular events. Dr Carolyn Lam: Okay, so drum roll. What did they find? Dr Greg Hundley: So, measurement of total cholesterol and HDLC in the non-fasted state is sufficient or was sufficient to capture the lipid associated risk in the cardiovascular disease prediction with no meaningful improvement from addition of APO lipoproteins, direct or calculated LDLC. And, similar findings were reproduced in those taking a statin at baseline. As such, the authors feel like calls for widespread use of APO lipoproteins are not warranted given the negligible difference in risk prediction beyond total cholesterol in HDLC. And, direct LDLC is also not required for risk prediction. Non HDLC is a cheaper or equivalent predictor of risk on and off statins without the requirement of one of us being fasting. This is an excellent article for our listeners to review or download. Dr Carolyn Lam: Wow, that is so cool. So, from one excellent paper to another excellent paper in our feature discussion. Let's go, shall we? Dr Greg Hundley: Welcome everyone to discussion of our featured article. We have Dr Kelley Branch from the University of Washington and our own Carolyn Lam, and they're going to be discussing the compass trial. So Kelley, could you tell us a little bit about the rationale for compass as opposed to the previously published commander study? Dr Kelley Branch: So, in order to understand compass and compare it to commanders, we're going to have to go back a little bit in time here. And recall, you know well over 20 years ago that when we used anticoagulants in coronary artery disease, that was actually shown to be more beneficial than aspirin alone, but because of the excess bleeding risk, warfarin or vitamin K antagonists not used, and aspirin won. Fast forward a number of years, and now we have the non-vitamin K anticoagulants, and the was potentially that we could find the goldilocks, if you will, the good balance of benefit as well as less bleeding maybe used to these new agents. So, the compass trial was really born from an atlas ACS one and Atlas ACS two, which found that a low dose of, in this case, Rivaroxaban 2.5 milligrams VAB as well as five milligrams VAB were shown to be beneficial in patients after acute coronary syndrome. And then, it was thought what happens if we treat these patients with now chronic coronary disease as well as arterial disease? And from this 27,000 patients, 47,395 patients were tested, and our study very specifically looked at patients with a baseline or a history of heart failure when they answered compass. Compass were shown to be beneficial with specifically the use of aspirin plus Rivaroxaban, 2.5 milligrams BAD. And, our idea was to test this in patients with this baseline or history of heart failure. Now, this is in real contradistinction to what the commander tried to do. And the reason why encompass, we actually excluded patients with severe heart failure. This was defined as a New York Heart Association class three or four or an ejection fraction less than 30%. Now if you looked at patients with commander, these patients had ejection fraction less than 40%. That was a criteria to get in. And of course, these patients had to have a recent hospitalization for heart failure. So, these are very different patient populations. Well, both of them, yes, they did have coronary artery disease, but really very different patient populations. Dr Greg Hundley: Very good. So Kelley, tell us specifically, what were your treatment group assignments and the doses and the outcomes that you were going to follow, and then lead us into what did you find? What were the outcomes of your study? Dr Kelley Branch: Sure, so compass was actually developed as a partial three by two factorial. The arm that we're going to be talking about is the rivaroxaban arm. There was also another arm that tested the use of Proton pump inhibitors, and that actually was shown to not be as beneficial as we thought to decreased bleeding. But specifically for rivaroxaban, the baseline was aspirin, and this was on top of guideline based medical therapy. And then patients were randomized to either aspirin alone plus placebo or Rivaroxaban, five milligrams BAD, plus placebo. So, no aspirin at all or aspirin, a hundred milligrams daily, plus Rivaroxaban, 2.5 milligrams BAD. Those were really the three treatments. Patients were going to be followed for about three to four years. That's what we expected to get our 2200 events , an event-driven trial. But, because of the overwhelming benefits at 23 months median follow up, this trial was actually stopped early, so we only had a little over 1300 events at that time. And with that we saw substantial reduction in major adverse cardiovascular events, about 24% mortality was reduced 18%, and there was a bleeding risk along with this, major bleeding, little different way of actually measuring major bleeding, but that was increased by about 70%, and that was the overall trial results. So, looking at the patients with heart failure, though, there was actually a relatively large proportion of patients, so 5,902 patients, about 22% of patients, actually had either baseline heart failure or had a history of heart failure coming in. Now, this was defined specifically by the PI's. These were not rigorously defined as compared to say commander, but these were patients where the PI said this patient has history or has chronic heart failure. So, with these 5,902 patients, we looked specifically at the outcomes of major adverse cardiovascular events similar to what we saw with compass and that is cardiovascular death, myocardial infarction, or any stroke, that combination. And then, looked at some others exploratory analysis like mortality. And, what we found is that in patients with heart failure, the baseline rate was substantially higher for a mate's. Not too surprising because this tends to be a higher risk patient population. But, what we found is that the hazard ratio was about 0.68, so pretty similar to what we've seen the 24% relative risk. In this case, this was a 32% relative risk reduction in those patients with heart failure. Now, if we looked at a patients without heart failure, the hazard ratio is 0.79, so fairly similar and the [conference intervals 00:16:33] overlap. No statistical heterogeneity or no difference between those, but what we did see if we looked at the absolute risk reduction, was an absolute risk reduction in heart failure of 2.4% reduction. That means a number needed to treat of about 42. If you look at the absolute risk reduction for those patients without heart failure, that was 0.9 to 1.0 depending on what the rounding was. We took 1.0 so that means the number needed to treat of 103. So, these were slightly different relative risks, but overall, what we saw is that the hazard ratio is very consistent with the overall effect of compass in the same direction. Interestingly, and actually I think even for me it was surprisingly, we actually looked at the hazard ratios for bleeding, and when we looked at the hazard ratios for bleeding, we fully expected that because it's the higher risk patient population, we actually expected that to go up. What we saw is that the bleeding actually was no difference at all, and if anything in the heart failure population was slightly lower. And, this was fairly surprising to us because we thought that the patients with heart failure, the bleeding would actually trend up because this was a higher risk patient population. So it looks like it's something can be used and really no substantial increase in bleeding. Dr Greg Hundley: Very good. Well Carolyn, as someone that's managing patients with heart failure, what do you see are the clinical implications of this study? Dr Carolyn Lam: That is a beautifully simple, direct question but is not as easy to answer as I may have thought. And, that's because the commander trial that Kelley did describe a bit earlier was neutral on its primary outcome. And, the commander trial is what we would traditionally think of as a heart failure trial. And why? Because those were patients that we rigorously define heart failure, including a naturally acid peptide inclusion criteria. And, because we really wanted these to be severe heart failure patients, we recruited them very close to their hospitalization or decompensation event. So, I just want to reiterate what Kelley has already so beautifully described that commander was neutral, whereas this heart failure subset of compass showed very impressive results that were consistent with the very impressive positive results of the overall compass trial. So, how do we reconcile all of it? Well, first of all, I have to humbly remind myself that this heart failure subset of compass, the entire subset was actually bigger in numbers than the entire of the commander trials. So, this is not a small little subgroup analysis. This is a huge subgroup analysis. And that's why a paper like this, we're so proud to be publishing in circulation. So, how do I apply it? Well, when I have a compass like patient, which means it's a stable coronary artery disease or peripheral artery disease patient who happens to have some mild heart failure. I think of this patient as a compass patient and I think that the combination of aspirin and low dose Rivaroxaban has been shown to be effective in these patients. So, in such a patient, I continue the aspirin rivaroxaban combination. However, if I have a new patient coming in with decompensated heart failure, a very low ejection fraction and has some coronary artery disease, by the way, I see that as a commander patient, and I just want to make sure that in such a patient I'm not trying to reduce their overall mortality by treating them with a combination of aspirin Rivaroxaban because commander has shown that I don't impact their overall survival with this combination, even though we may still have beneficial effects on their thromboembolic thrombotic events. Kelley, would you agree? Dr Kelley Branch: I would completely agree. That was actually born out very, very well by Barry Greenberg who had a really a wonderful sub analysis which he looked at the thrombotic events published in Jama cardiology and really showing that yes, you can affect the thrombotic events, but I mean really what it comes down to is we want to save lives. We want people to be better. There's just an overwhelming risk for these patients with heart failure that is really non thrombotic, primarily. And so, you're really not going to move the needle very much. You may prevent a stroke here, you may prevent some cardiovascular death from a thrombotic problem, but overwhelmingly pump failure, arrhythmia, et cetera. Those are really going to be the drivers for the commander like population. Dr Carolyn Lam: But Kelley, this comes up a lot when we've chatted, but if you have a compass patient who has heart failure and then gets admitted with heart failure, what would you do then? Dr Kelley Branch: That's a really interesting question, right? It depends on what the overall goal is. So, if the patient gets admitted for heart failure, now has it decreased ejection fraction sick. So has an MI, now decreased the ejection fraction. What's the end game? Right? Well you know, you may not be affecting mortality in this case because there's now competing events. However, if the goal was to decrease stroke, we've seen that. Still this goal is to decrease MI to some extent than we see that also. So, it would be reasonable to continue in order to prevent those events. But, just knowing full well that there's many other medications which actually do much better for the patients with decreased ejection fraction. And, those would probably be considered first line, but it's reasonable to continue. But, I would never start it. Dr Carolyn Lam: Kelley, I couldn't agree more. And here I think the, your data showing that the bleeding risk is not significantly increased in this patient matters a lot. So, if I had a patient, a compass patient who was already on the combination and then gets admitted with heart failure, I too, if there's no additional bleeding risk, I would continue the combination as well. Dr Kelley Branch: Couldn't agree more. Dr Greg Hundley: Well listeners, this was a fantastic discussion, and we look forward to seeing you next week. Have a great week. Dr Carolyn Lam: This program is copyright American Heart Association 2019.

Circulation June 11, 2019 Issue

Play Episode Listen Later Jun 10, 2019 20:48

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summery and backstage pass to the journal and it's editors. We're your co-hosts, I'm Doctor Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Gregory Hundley: And I'm Doctor Greg Hundley, Associate editor for Circulation and Director of the Pauley Heart Center at VCU of Health in Richmond, Virginia. Well Carolyn, in the second half of our feature we're going to discuss a randomized clinical trial in lower risked surgical patients related to, the five year clinical echocardiographic outcomes from aortic valve intervention. So Carolyn, do you want to go first this time and discuss on of your favorite papers? Dr Carolyn Lam: Absolutely! So, are Cardiac Troponin T and I equivalent measures of cardiovascular risk in the general population? Well that's the question Doctor Paul Welsh and colleagues from University of Glasgow aimed to look at. They wanted to compare and contrast the associations of Cardiac Troponin T and Cardiac Troponin I with cardiovascular disease and non-cardiovascular disease outcomes, and also determine their genetic determinants in a genome wide association study involving more than nineteen-thousand, five hundred individuals in generation Scotland, Scottish family health study. Dr Gregory Hundley: How about that. So this is kind of interesting. So most of us kind of use these two chests interchangeably Carolyn, and I think, I guess we'd consider them to be almost equivalent. So are you going to tell us that they are the same? Dr Carolyn Lam: Ah-hah! So this is what the authors found. Both Cardiac Troponins T and I were strongly associated with cardiovascular risk, however, Cardiac Troponin I but not T was associated with both myocardial infarction and coronary heart disease. Both Cardiac Troponins I and T had strong associations with cardiovascular death and heart failure, however, Cardiac Troponin T, but not I was associated with non-cardiovascular disease death. They also identified five genetic loci in fifty-three individuals snips that had GWAS significant associations with Cardiac Troponin I and a different set of four loci of four snips for Cardiac Troponin T. So, the upstream genetic causes of low-grade elevations of Cardiac Troponins I and Cardiac Troponin T appear to be distinct and their associations with outcomes also differ. Elevations of Cardiac Troponin I are more strongly associated with some cardiovascular disease outcomes whereas Cardiac Troponin T, is more strongly associated with the risk of non-cardiovascular disease death. These findings can help inform selection of an optimal Troponin essay for future clinical care and research in these settings. Dr Gregory Hundley: Very good! So, does sound like there could be a little bit of a difference, depending upon what outcome you're looking for. So, Carolyn I'm going to discuss a paper from Doctor Alison Wright and colleagues at the University of Manchester, and it involves cardiovascular risk and risk factor management in type two diabetes. So in this retrospective cohort study, using the clinical practice research data link, linked to hospital and death records for people in England, investigators identified 79,985 patients with incident type two diabetes, between the years 2006 and 2013, matched to three 386,547 patients without diabetes, and sex-stratified Cox models were used to assess cardiovascular risk. Dr Carolyn Lam: Oh I'm dying to know, what did they find? Dr Gregory Hundley: Well compared to women without type two diabetes mellitus, women with type two diabetes mellitus had a higher cardiovascular event risk than the adjusted hazard ratios 1.2, with similar corresponding data in men, so their hazard ratio is 1.1. And that lead to a nonsignificant relative risk in women with a risk ration of 1.07, however, some important sex differences in the management of risk factors were observed. Compared to men with type two diabetes, women with type two diabetes were more likely to be obese, hypertensive, and have hypercholesterolemia but were less likely to be described lipid lowering medication, ace inhibitors, especially if they had cardiovascular disease. So Carolyn, compared to men developing type two diabetes mellitus, women with type two diabetes mellitus do not have a significantly higher relative increase in cardiovascular risk, but, ongoing sex disparities in prescribing should prompt heightened efforts to improve the standard and equity of diabetes care in women as compared to men. Dr Carolyn Lam: Nice Greg. Important message. My next one has an important message too. Now it goes to the pediatric population now. We know that brain injury, impaired brain growth, and long term neuro development problems are common in children with transposition of the great arteries. Now does the age at arterial switch operation predict these neuro developmental outcomes in infants with transposition of the great arteries or TGA? Well Doctor Mike Seed from Hospital for Sick Children in Toronto, Canada and colleges addressed this question by imaging the brains of 45 infants with TGA, undergoing surgical repair, pre and post operatively using MRI. Their main finding was that surgery beyond two weeks of age is associated with impaired brain growth and slower language development in infants with TGA. Dr Gregory Hundley: Wow Carolyn, this seems like, this could have really important clinical implications for the management of these patients. Dr Carolyn Lam: Yeah, indeed. Expediting surgical repair could be neuro protective in newborns with Transposition. While the mechanisms underline this association are still unclear, extended periods of cyanosis and pulmonary over circulation maybe factors that inversely impact brain growth and subsequent neurodevelopment if the surgery's not done early. The timing of surgery may have an impact on neurodevelopment in other forms of congenital heart disease, too, therefore. So all of this is discussed in an editorial entitled Correction of TGA, "Sooner Rather than Later?", and this is by Doctors Rollins and Newburger, from Boston's Children's Hospital. Dr Gregory Hundley: Fantastic Carolyn, well I'm going to discuss a paper from the World of Basic Science from the Ohio State University, Wexner Medical Center from Doctor Douglas Lewandowski. And it involves the preservation of Acyl-CoA and how that attenuates pathological and metabolic cardiac remodeling through selective lipid trafficking. So Carolyn, it has been shown that metabolic remodeling in heart failure contributes to dysfunctional lipid trafficking, and lipotoxicity. Acyl-Coenzyme A Synthase One, or ACLACSL1 facilitates long chain fatty acid uptake an activation with coenzyme A, mediating the fate of the long chain fatty acids. The authors tested wither cardiac Acyl coenzymes A synthase One over-expression aided long chain fatty acid oxidation and reduced lipotoxicity under the pathologic stress of transverse aortic constriction or TAC. Dr Carolyn Lam: Interesting, I like that concept of metabolic remodeling. So what did they find? Dr Gregory Hundley: So Carolyn, the studies were performed in both mice and in human subjects, and in mice at 14 weeks, TAC induced cardiac hypertrophy and disfunction was mitigated in MHCACSL1 hearts compared to nontransgenic hearts. This was manifest by retain greater rejection fraction, 65.8 percent versus the nontransgenic hearts of 45.9 percent. An improvement in diastolic E over E prime. Also, functional improvements were mediated by ACSL1 changes to cardiac long chain fatty acid trafficking. In humans, long chain Acyl-CoA was reduced in human failing myocardium and restored to control levels by mechanical unloading. So, Carolyn, this is the first demonstration on reduced Acyl-Co-A in failing hearts of humans and mice, and suggest possible mechanisms for maintaining mitochondrial oxidative energy metabolism by restoring long chain Acyl-CoA through ASCL1 activation and mechanical unloading. Dr Carolyn Lam: Awesome Greg! Thanks so much for sharing that paper. Let's go on to our feature discussion. Dr Gregory Hundley: You bet. Dr Carolyn Lam: Our feature discussion today is about transcatheter aortic-valve replacement. Could this be the new gold standard for the treatment of aortic stenosis? And yes, I am borrowing from the title of the editorial that accompanies our feature paper. With the editorialists right here with us, Dr Bernard Prendergast, from Saint Thomas' Hospital in London, and we are talking about the wonderful paper for the notion trial and that's a Nordic aortic valve intervention randomized clinical trial, and we're here with the first and corresponding author of that paper Dr Hans Gustav Thyregod from Copenhagen University Hospital, and we also have our associate editor Dr Dharam Kumbhani from UT Southwestern. So welcome gentlemen! And for a start could I ask Hans to please describe the results of the notion trial. Dr Hans Thyregod: The notion trial as you said is the Nordic aortic valve intervention trial. Designed to compare transcatheter therapy and surgical therapy and patients with severe aortic valve stenosis, patients have to be thirteen years old or older and we didn't really specify any risk profile, as in previous trials. So all patients eligible for both procedures would be enrolled in the trial. And the main result of the trial was that we couldn't find a difference when looking at the composite outcome, which was all-cause mortality, stroke American infraction. The primary outcome was after one year, in this paper it's up to five years and we could not see any difference. So the range was, in my estimate was 38 percent for transcatheter therapy versus 36.3 percent for surgery. And when looking at the different components of this composite outcome, all-cause mortality, stroke American infraction. We couldn't find any surgically significant difference for any of those outcomes either. Dr Carolyn Lam: Wow, Bernard, could I ask you to place these results into context for us, I mean the notion trial is after all the first to compare TAVR and SAVR in patients with severe isolated valve stenosis at lower surgical risk, and really has the longest follow-up doesn't it? So please tell us, what are your thoughts? Dr Bernard Prendergast: So this is yet another notch the remarkable success story of TAVI or TAVR, as you call it in the U.S. We pass our congratulations from the community to Dr Thyregod and the team in Copenhagen for such a ground-breaking study. The wider context is he say is the TAVR have demonstrated remarkable efficacy and safety, initially in operable and high-risk patients, but, more recently randomized control trials in intermediates and lower risk patients. And the important perspective of this study provides is the longer term follow up, because for a number of years we've perhaps considered TAVI or TAVR as a, let’s say a shorter-term treatment for patients in their eighty's and older, who perhaps have a shorter life expectancy. But what the five-year data demonstrates to us is that TAVI or TAVR is as good as surgery, at five years of follow up. With very reassuring outcomes, they maintain durability of the transcatheter heart valve, that's highlighted in the companion paper, which, is published very recently in JACC. So really takes TAVI into a new territory, which is patients who have at least five years or longer to live and allows us to extend the indication for the procedure into younger patients. Alongside lower risk patients, who have supported by the recent landmark studies published in the New England Journal from Partner Three, and the Core Valve Low Risk trial. So, the information is very reassuring and it's another very positive notch in the journey of TAVI across the spectrum of surgical risk. Dr Carolyn Lam: Thank you! Beautifully put and Dharam could I just ask you I mean what more do we need? Do you think this is guideline defining stuff now? Or do you have questions? Dr Dharam Kumbhani: I really want to congratulate the investigators of the NOTION trial, as far as providing us with this longer term follow up in a lower risk population, and so, you know the field is moving incredibly, incredibly quickly and you know as we just mentioned TAVR has now gone from being something that's done in patients that are too high risk to level convention surgery, to now perhaps becoming either one of the main stream options, or the main stream option. And you know time will tell, so I think what this study really helps us is, provide us with a five-year time horizon on follow up, but, to be fair, you know this trial is very helpful in certain ways because it was designed a few years ago. You know it was done with the generation of a valve that is not used much right now for the most part, and you know so it's some of the things like pacemaker et cetera, may not translate to current practice. Even though the clinical outcomes were similar, it's probably some issues with power as well, but, again not in a clinical way, but, just to kind of say that this trial definitely helps us in moving the field forward and it kind of adds to the growing body of literature that supports that. Going forward I guess one question I would have for this group is, you know as we think about TAVR and surgical aortic replacement, it would seem that we would need even longer term data, based off of detonators to be able to confidently tell patients, there are fairly similar therapies. And then the other question is, this construct of surgical risk is that we applied telegraphically based on how the evolution of TAVR has occurred, but one wonder, you know with NOTION and other trials we should be thinking about this perhaps from an age perspective as a sort of NOTION trial—those would be my two comments. Dr Bernard Prendergast: I think that's a very valuable comment, and of course there are other ongoing trials, which, will help to address many of these questions. One important deficit of notion is that it didn't enroll, for example, patients with bicuspid aortic valves. And we know that bicuspid aortic stenosis is far more common in younger patients. So, Hans a few comments regarding the protocol for notion two maybe helpful for our listeners. Dr Hans Thyregod: Well this was mentioned, the follow up of five years is obviously not a very long time in younger patients with a lower risk profile. We are planning to follow these patients for at least 10 years. And the other comment about the risk profile of the risk certification of patients is also very interesting because the SDS and your scores have been developed for surgical patients and not for transcatheter patients. So we need a whole new transcatheter risk scoring system to help our team determining what treatment would be the best suited for each patient. And as Dr Prendergast mentioned we are in Copenhagen, and Scandinavia conducting a NOTION II trial, which, will enroll patients younger than the previous low risk trials and also the notion trial. Which, at a mean age, at least for the patient of around 80 years and in notion two patients must be younger than 75 years old. And we are also including patients with bicuspid valve stenosis, and also patients which were not included in the NOTION I trial. Patients with a coronary artery disease, so these patients are obviously also a different patient category and will maybe require a different approach regarding the timing of the revascularization and so forth so there is more research to be done in those areas. Dr Carolyn Lam: Well exciting. Thank you for sharing that Hans. Dharam could I ask you to just wrap us up with the take home message, it's for our audience right now. Dr Dharam Kumbhani: For me one of the most interesting findings was that in five years, the clinical performance between TAVR and SAVR were similar, but, more importantly the valve performance, the hemodynamic performance was the same, and perhaps slightly better with the self-expanding design. They are so proud of the self-expanding design that was studied in the study. So that is helpful because as we discussed earlier, I think a lot of the controversy discussions centers around the long-term durability of TAVR compared with surgically aortic valve replacement, so that is a step in the right direction. The same investigators have published that hemodynamic performance elsewhere as well, sot that's I think the number one take home message that, that's very, very reassuring. The second thing is you know this study shows us it adds to the growing body of literature, in lower risk patients so all of this was not strictly a lower risk trial based on contemporary definition. It was definitely a lower risk population and so, this is the largest pool of patients where they aortic stenosis about 50 percent will have low risk aortic stenosis, low surgical risk aortic stenosis and so this is very helpful in that space and then third you know that this is very exciting that NOTION investigators indeed are the low risk trial investigators, will be extending their follow up with 10 years. So I think in this next decade, most people expect as Dr Prendergast also mentioned, we'll see a gradual change perhaps in how patients with aortic stenosis manage. But, I will add a word of caution, I think in the current era, the way things stand right now, it's probably best in favor to appeal to what the guideline indicates. And for the low risk patients, surgical aorta valve replacement is still the center of choice. Dr Carolyn Lam: Thank you so much Dharam and thank you Hans for the beautiful paper, and Bernard for that excellent editorial! Thank you audience for joining us today, you've been listening to Circulation on the Run. Don't forget to tune in again next week. This program is copyright American Heart Association 2019.

Finale A with Paul Welsh and Madeline Walter

Everything Is Rent

Play Episode Listen Later May 14, 2019 71:52

Sarah and Beth are joined by their dear friends, Paul Welsh and Madeline Walter (Brooklyn Nine-Nine). Madeline, who is convinced Jonathan Larson didn't write all the songs in Rent, talks about only liking the first half of the show and Paul, who thinks Ellen DeGeneres was in Rent, explains why he was so angry when "Seasons of Love" came on the radio recently. There's also an extended discussion of weird onstage kisses between brothers and sisters and age-inappropriate people. Paul shares what it was like acting alongside Broadway actors on Crazy Ex-Girlfriend and Madeline tells a story about breaking someone's front teeth during an audition for Funny Girl. Listen for your chance to win a 311 CD and a sleepover! -- SHOW INFORMATION Instagram: @EverythingIsRent Twitter: @Everything_Rent Email: EverythingIsRentPod@gmail.com Subscribe: Apple Podcasts Subscribe: Spotify

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The Big Fish Shark Yak Attack

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Play Episode Listen Later Feb 22, 2019 60:00

This week on The Big Fish we look at the Shark activity off Sydney with the Stealthy kayak Fisher Paul Welsh. As you can see the fishing tax collectors in the grey suits take their cut from time to time.

The Best of Meta Vol. 1

Play Episode Listen Later Feb 6, 2019 144:11

Please enjoy volume one of the all-time best i4h scenes about improv, Matt Besser, Earwolf, and all things meta! This compilation features amazing performances by Tim Meadows, Joe Wengert, John Gemberling, Zach Woods, Colton Dunn, Charlie Sanders, Sean Conroy, Billy Merritt, Paul Rust, Mike Mitchell, Mike Hanford, Dave Ferguson, Dominic Dierkes, Sean Clements, Drag The River, Seth Morris, Jon Gabrus, Ben Schwartz, Gil Ozeri, Mookie Blaiklock, Dan O'Brien, Danielle Schneider, Jessica St. Clair, Lennon Parham, Jason Mantzoukas, Austin Lucas, Jon Snodgrass, Andy Daly, Peter Gwinn, Amanda Sitko, Andy Secunda, Mary Holland, Dan Lippert, Molly Bretthauer, and Paul Welsh.This episode is sponsored by Squarespace (www.squarespace.com/IMPROV code: IMPROV).

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The Best of Meta Vol. 1

Play Episode Listen Later Feb 6, 2019 139:29

Please enjoy volume one of the all-time best i4h scenes about improv, Matt Besser, Earwolf, and all things meta! This compilation features amazing performances by Tim Meadows, Joe Wengert, John Gemberling, Zach Woods, Colton Dunn, Charlie Sanders, Sean Conroy, Billy Merritt, Paul Rust, Mike Mitchell, Mike Hanford, Dave Ferguson, Dominic Dierkes, Sean Clements, Drag The River, Seth Morris, Jon Gabrus, Ben Schwartz, Gil Ozeri, Mookie Blaiklock, Dan O'Brien, Danielle Schneider, Jessica St. Clair, Lennon Parham, Jason Mantzoukas, Austin Lucas, Jon Snodgrass, Andy Daly, Peter Gwinn, Amanda Sitko, Andy Secunda, Mary Holland, Dan Lippert, Molly Bretthauer, and Paul Welsh. This episode is sponsored by Squarespace ( www.squarespace.com/IMPROV code: IMPROV).

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The Big Fish Extreme Yak

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Play Episode Listen Later Dec 14, 2018 60:00

On TBF this episode extreme yak fishing with Paul Welsh, tips for Mum's fishing with their kids from Jo Starling our fanatical fisherwoman, Stinker with more tales of monsters from the deep and Craig McGill shares a sneaky squid jig rig that will have you catching cephalopods by the bucket full.

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42- Jesus Tree w/ Paul Welsh (Crazy Ex-Girlfriend)

A Funny Feeling

Play Episode Listen Later Jul 17, 2018 60:06

Betsy and Marcy catch up on some listener ghost stories!We have our dear friend Paul Welsh (Crazy Ex-Girlfriend) with stories of spooky Connecticut and a very interesting discussion about the politeness of ghosts! And we have a listener story from Emily who stayed at the haunted old Governor's mansion in Maine!Please send us your own true paranormal experiences in either a voice memo or e-mail to funnyfeelingpod@gmail.com.

145 - Paul Welsh - Sons Of Arnachy - Small World

It's That Episode

Play Episode Listen Later May 26, 2018 57:05

Paul Welsh (Crazy Ex-Girlfriend) stops by to watch Sons of Anarchy.

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255 - Lonewolf Champion Paul Welsh

Ohiohammer - The 9th Age Podcast

Play Episode Listen Later May 12, 2018

Tonight we are joined by the newly christened King of Texas, er Lonewolf Champion, Paul Welsh. Paul breaks down his experience in the US and his time at the Lonewolf GT in Fort Worth, Texas. Sit back and enjoy!

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255 - Lonewolf Champion Paul Welsh

Counter Charge - Your Podcast For All Things Kings of War

Play Episode Listen Later May 12, 2018

Tonight we are joined by the newly christened King of Texas, er Lonewolf Champion, Paul Welsh. Paul breaks down his experience in the US and his time at the Lonewolf GT in Fort Worth, Texas. Sit back and enjoy!

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89 - Paul Welsh and Madeline Walter in Holiday Extravaganza!

The MEAT Improv with Jake Jabbour and Josh Simpson

Play Episode Listen Later Dec 19, 2017 85:23

Meathead favs, and all around comedic genius' Madeline Walter (Weeds, The Defenders, Childrens Hospital) and Paul Welsh (Crazy Ex-Girlfriend, Broad City) talk holiday traditions with child servants, elaborate theatre, and of course teacher wieners! Give a listen this holiday season and share with your friends and family to be the talk of the town! For information regarding your data privacy, visit acast.com/privacy ( https://www.acast.com/privacy ) Support this podcast at — https://redcircle.com/the-meat-improv-with-jake-jabbour-and-josh-simpson/donations Advertising Inquiries: https://redcircle.com/brands Privacy & Opt-Out: https://redcircle.com/privacy

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Jess Dweck / Paul Welsh

Baby Geniuses

Play Episode Listen Later Oct 16, 2017 82:54

Hello babies! What is your word of the year? We have a few fun and totally not sad options for this year. Emily has a weird, creepy experience with some curtains. Curtains aren’t supposed to do that! Lisa gets a terrible DM on Instagram. On Wiki of the Week, we read the Wikipedia page for “List of premature obituaries.” A premature obituary is an obituary published whose subject is not actually deceased at the time of publication. Who knew not dying could be so fun? We welcome “writer” Jess Dweck who had a particularly bad Airbnb experience. On Expert Hour, we are joined by Ricky Tarps, who gives us some creative pointers on how to eat on a budget. Emily Heller Lisa Hanawalt Jess Dweck Paul Welsh

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Episode 20: Fools review and hobby with Paul Welsh

FourFootSnake's podcast

Play Episode Listen Later Apr 12, 2017 56:49

Episode 20: Fools of War, AltiBash4 and hobby chat with Paul Welsh A Kings of War (KoW) podcast, with Nick, Jon, Dan and Matt (who?) In Episode 20, Jon, Nick and Dan chat to KoW newcomer (and superb painter / hobbyist) Paul Welsh. Paul's Varangrrr army has been winning admiration on KoW Fanatics and having already claimed a win vs. Dan he is rapidly becoming a great KoW player. Nick, Dan and Paul talk about the recent two-dayer, Fools of War and we have a preview of the upcoming AltiBash4 event. Hobby is focused on preparation for the upcoming Lonewolf GT, with Dan and Nick having quite of work to do (and smug Jon realising that he still has lots to do too..). Edited bits: No edits and boy can you tell... sound levels were hard to balance due to laughter throughout Event links AltiBash4 Haven from the Storm Lonewolf GT Feedback: We welcome messages on Facebook or Twitter. If you'd like us to cover your event or want some advice on army building, playing or painting.. get in touch. Facebook: www.facebook.com/FourFootSnake/ Twitter: @ohfourfootsnake

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Jackie Kashian / Paul Welsh

Baby Geniuses

Play Episode Listen Later Mar 20, 2017 89:32

Hello babies! It’s MaxFunDrive 2017- go to Maximumfun.org and help support the Babies and all your other favorite shows! Check out the Baby Geniuses themed gifts! I want a Baby Geniuses butt pin really badly!! We’re traveling a lot this month which has us wondering - how do you pronounce this dang place? Do you make an effort to do as the locals do? When in Rome, say Roma? Or does “Paris” rhyme with “heiress” to you? Emily finally got around to seeing A Dog’s Purpose. On the subject of gut wrenchingly bad movies, we respond to feedback we received about our La La Land opinions. On Chunch Chat, Martha adds some colorfully named fowl to the coop. On Wiki of the Week, we read the Wikipedia page for “Concealed Shoes,” or shoes that are hidden inside buildings while they are being constructed. We welcome Jackie Kashian, who is not ashamed to tell us about her love of Romance Novels. On Expert Hour, dessert medium Roy Lips joins us to share how he uses sweets to connect us with the deceased. Emily Heller Lisa Hanawalt Jackie Kashian Paul Welsh

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37 - The Best of 2016 Fine Cuts MEATStravaganza - Part 1

The MEAT Improv with Jake Jabbour and Josh Simpson

Play Episode Listen Later Dec 27, 2016 70:57

Josh and Jake present the first of two very special episodes featuring some of the funniest scenes and stories from 2016. Featuring Mary Holland, Nicole Byer, Allan McLeod, Beth Appel, Kirby Howell-Baptiste, Mary Sasson, Dan Lippert, Joel Jensen, Matt Rath, Naomi Villa, Kale Hills, Marcy Jarreau, Jace Armstrong, Ally Beardsley & Paul Welsh! This episode is dedicated to Gian Molina, a fantastic improviser and an even better friend who passed away on December 20th, 2016. Rest in Peace, Gian. For information regarding your data privacy, visit acast.com/privacy ( https://www.acast.com/privacy ) Support this podcast at — https://redcircle.com/the-meat-improv-with-jake-jabbour-and-josh-simpson/donations Advertising Inquiries: https://redcircle.com/brands Privacy & Opt-Out: https://redcircle.com/privacy

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9: The Value of Switching It Up (w/ Paul Welsh)

The Dumbbells

Play Episode Listen Later Dec 21, 2016 70:01

Episode 9 is here! Paul Welsh (co-host of the Hard Nation podcast and Trent from My Crazy Ex-Girlfriend) charges into the Weight Room and schools The Dumbbells on why he is always changing up his workouts. The group talks about the value of periodically using a trainer, Pauls background in competitive swimming and a lot of time is spent on improv team names. Then the DBs and Paul give some advice on what to do when you plateau and last they answer questions on flexibility and the necessity of getting 10,000 steps a day. "I command you to grow!!!!!" Subscribe, Rate & Review The Dumbbells on iTunes Twitter: @thedumbbells Instagram: @thedumbbells Facebook: The Dumbbells *Tag us with all you fitness pictures and don't forget #picsoritdidnthappen * Have a fitness/nutrition question? Shoot the Dumbbells an email: AsktheDumbbells(at)GMAIL(dot)com

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Mr Oregon, Paul Welsh

Mystic Party

Play Episode Listen Later Dec 3, 2016 66:31

Randy Oregon is haunted by the ghosts of neglected pets past. See acast.com/privacy for privacy and opt-out information.

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07 - Beth Appel and Paul Welsh in "Dads and Chads"

The MEAT Improv with Jake Jabbour and Josh Simpson

Play Episode Listen Later May 31, 2016 84:16

True stories about losing loved ones and head injuries lead to scenes about Denver's finest improv team, rabbit hutches, principals that party and more! For information regarding your data privacy, visit acast.com/privacy ( https://www.acast.com/privacy ) Support this podcast at — https://redcircle.com/the-meat-improv-with-jake-jabbour-and-josh-simpson/donations Advertising Inquiries: https://redcircle.com/brands Privacy & Opt-Out: https://redcircle.com/privacy

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Mike Still, Paul Welsh, Jessica McKenna

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Play Episode Listen Later May 18, 2016 84:32

Mike Still, Jessica McKenna and Paul Welsh join Matt Besser on this week's improv4humans. They improvise about the musical number in Virgin Airlines' safety video and explore new weight loss challenges. People running for U.S. Senate inspire a scene about presidential candidates' opening statements in a debate. Also, an unhelpful employee starts a new job writing for improv4humans.See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

Mike Still, Paul Welsh, Jessica McKenna

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Play Episode Listen Later May 18, 2016 90:05

The Stegosaurus Challenge - Mike Still, Jessica McKenna and Paul Welsh join Matt Besser on this week's improv4humans. They improvise about the musical number in Virgin Airlines' safety video and explore new weight loss challenges. People running for U.S. Senate inspire a scene about presidential candidates' opening statements in a debate. Also, an unhelpful employee starts a new job writing for improv4humans.

On The Cusp - Ep 024 - Paul Welsh

On the Cusp

Play Episode Listen Later Sep 30, 2015 72:04

Ben Greene interviews one of the members of the UCB House Improv Team JV, Paul Welsh. Paul is an actor/writer/improviser who has appeared on TV shows like Key and Peele, Children’s Hospital, and Broad City. He has written shows like “Paul Welsh Goes to a TED Conference” and “Men in Paintings: A Night at the Crisp Family Hall of Portraits.” In Ben’s interview with Paul, you’ll get to hear him talk about how sassy he was in elementary school, how many hours he’s put in tutoring high schoolers for the SAT, and how he almost humiliated himself in front of Megan Mullally.

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BA #091: Paul Welsh

Box Angeles

Play Episode Listen Later Aug 7, 2015 83:07

Actor Paul Welsh (Key and Peele, Playing House) stops by Studio 309 and discusses working for a hedge fund in NYC, diving in fully at UCB, and more! Info, photos, links, et cetera -- http://boxangeles.com/2015/08/10/ba-091-paul-welsh/

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Seeing Into Space: Perspectives and Initiatives for Enhancing Space Situational Awareness

SWF Podcast

Play Episode Listen Later Jan 6, 2015 117:57

Recorded December 9, 2014 Space situational awareness (SSA) - commonly defined as knowledge about the space environment and activities in space - is an important part of space sustainability, safety, and security. SSA has historically been mostly a military mission that focused on tracking the locations of objects in space and detecting space-based threats. However, the nature of SSA is evolving as the number of actors in space increases, including an increasing proportion of non-governmental players and space activities, and the nature of the threats to active satellites diversifies and expands to include natural and human-generated threats, as well as intentional and unintentional threats. Secure World Foundation (SWF) held a luncheon panel discussion to discuss the changing nature of SSA and examine initiatives being developed by both the U.S. government and non-governmental entities to enhance SSA. For more information, please visit the event page. Panel 1 - Established Services, Providers, and Policies Mr. Richard Buennneke, Senior Advisor for National Security Space Policy in the Bureau of Arms Control, Verification and Compliance, U.S. Department of State Mr. John Hill, Principal Director, Space Policy, Office of the Under Secretary of Defense for Policy, U.S. Department of Defense Mr. Andrew D'Uva, President, Providence Access Company Panel 2 - Emerging Services, Providers, and Policies Dr. Michael Romanowski, Director, Commercial Space Integration, Federal Aviation Administration Mr. Paul Welsh, Vice President of Business Development, Analytical Graphics, Inc. (AGI) Mr. Matthew Bold, Chief Architect, Ground Based Space Situational Awareness (GBSSA), Lockheed Martin Advanced Technology Center The discussion was be moderated by Mr. Brian Weeden, SWF Technical Advisor.

Best of improv4humans Vol. 5

Play Episode Listen Later Jul 3, 2014 77:23

Best of improv4humans Vol. 5 - That time has come once again humans! The best of improv4humans with Matt Besser volume 5 is here featuring an amazing roster of the greatest improvisers in the universe including Joe Wengert, Sean Clements, Dominic Dierkes, Jason Mantzoukas, Lennon Parham, Jessica St. Clair, Jeff Hiller, Jon Gabrus, Mike Still, Tim Meadows, Horatio Sanz, Brian Huskey, Paul Rust, Mary Holland, Alex Fernie, Lauren Lapkus, Gil Ozeri, Johnny Meeks, Michael Delaney, John Gemberling, Zach Woods, Dan Lippert, Molly Bretthauer, and Paul Welsh. Plus, music from David Bazan and fucking with Eric the Intern. Make sure to get the UCB Comedy Improv Manual , Matt Besser’s new comedy album at mattbesser.com , and Dragoon’s new album at dragoongalaxy.bandcamp.com ! This episode is sponsored by Cards Against Humanity .

Best of improv4humans Vol. 5

Doodie Calls with Doug Mand

Play Episode Listen Later Jul 2, 2014 71:00

That time has come once again humans! The best of improv4humans with Matt Besser volume 5 is here featuring an amazing roster of the greatest improvisers in the universe including Joe Wengert, Sean Clements, Dominic Dierkes, Jason Mantzoukas, Lennon Parham, Jessica St. Clair, Jeff Hiller, Jon Gabrus, Mike Still, Tim Meadows, Horatio Sanz, Brian Huskey, Paul Rust, Mary Holland, Alex Fernie, Lauren Lapkus, Gil Ozeri, Johnny Meeks, Michael Delaney, John Gemberling, Zach Woods, Dan Lippert, Molly Bretthauer, and Paul Welsh. Plus, music from David Bazan and fucking with Eric the Intern. Make sure to get the UCB Comedy Improv Manual , Matt Besser's new comedy album at mattbesser.com , and Dragoon's new album at dragoongalaxy.bandcamp.com ! This episode is sponsored by Cards Against Humanity .See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

Doodie Calls - Paul Welsh

Play Episode Listen Later May 11, 2014 28:05

Doug sits down with comedian Paul Welsh (Playing House, Upright Citizens Brigade) to talk cell phone clogs, downhill emergencies and a not so friendly pop in.

Zach Woods,Nick Mandernach,Matt Newell,Erin Whitehead,Dan Lippert,Molly Bretthauer,Paul Welsh

psa vpn zach woods erin whitehead dragoons dan lippert matt newell nick mandernach paul welsh

Play Episode Listen Later Nov 6, 2013 74:22

Grab some snacks and buzz juice and listen to a special VPN edition of improv4humans with Zach Woods and UCB-LA Harold team members Nick Mandernach, Matt Newell, Erin Whitehead, Dan Lippert, Molly Bretthauer, and Paul Welsh! Theyll soothe a crowd of rioters with horn instruments, record a anti-diversity PSA, and be utterly mystified by Eric the (Un)paid interns vivid description of a rainbow party. Check out the full video over at youtube.com/earwolf ! You can now get the UCB Comedy Improv Manual ,Matt Bessers new comedy album at mattbesser.com , and Dragoons new album at dragoongalaxy.bandcamp.com !See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

Zach Woods,Nick Mandernach,Matt Newell,Erin Whitehead,Dan Lippert,Molly Bretthauer,Paul Welsh