Podcasts about pulmonary arterial hypertension

On this episode of JHLT: The Podcast, the Digital Media Editors invite author Ioana Preston, MD, to discuss the paper, “Efficacy and safety of sotatercept across ranges of cardiac index in patients with pulmonary arterial hypertension: A pooled analysis of PULSAR and STELLAR.”   Dr. Preston is the director of the pulmonary hypertension center at Lahey Hospital and Medical Center in Burlington, Massachusetts, and has over 20 years of experience in caring for patients with PH, as well as multiple clinical trials in PH.   The episode explores: What makes sotatercept unique as the first “biologic” in the treatment of PAH Hypotheses about the mechanism of action in sotatercept Sotatercept's interaction with mPAP and what it indicates about the drug's action on the pulmonary vasculature   For the latest studies from JHLT, visit www.jhltonline.org/current, or, if you're an ISHLT member, access your Journal membership at www.ishlt.org/jhlt.   Those involved in the heart failure and mechanical circulatory support should tune in again later this month for a study on apixaban plasma levels in patients with HeartMate 3 support.   Don't already get the Journal and want to read along? Join the International Society of Heart and Lung Transplantation at www.ishlt.org for a free subscription, or subscribe today at www.jhltonline.org.

Latest Developments in the Treatment of Pulmonary Arterial Hypertension    Guest: Robert P. Frantz, M.D. Host: Kyle Klarich, M.D.   Pulmonary arterial hypertension (PAH) is a serious disease manifested by vasoconstriction and obliteration of the pulmonary arterial vasculature resulting in rise in pulmonary artery pressure and resistance and culminating in right heart failure. Listeners will learn more about traditional treatments for PAH, as well as new anti-proliferative therapies in active clinical investigation, and what that means for the future of treatment.   Topics Discussed: What is most new and exciting in the treatment of pulmonary arterial hypertension? What monitoring is necessary in order to safely use sotatercept? What future developments do you envision for the field of pulmonary hypertension?   Connect with Mayo Clinic's Cardiovascular Continuing Medical Education online at https://cveducation.mayo.edu or on Twitter @MayoClinicCV and @MayoCVservices. LinkedIn: Mayo Clinic Cardiovascular Services Cardiovascular Education App: The Mayo Clinic Cardiovascular CME App is an innovative educational platform that features cardiology-focused continuing medical education wherever and whenever you need it. Use this app to access other free content and browse upcoming courses. Download it for free in Apple or Google stores today! No CME credit offered for this episode. Podcast episode transcript found here.

Returning for a second study this month, the JHLT Digital Media Editors conduct an internal discussion on the paper, “Safety and efficacy of riociguat in patients with pulmonary arterial hypertension and cardiometabolic comorbidities: Data from interventional clinical trials.”   The episode explores: The aging PAH population and the new comorbidities that must be considered in research How the study augments and expands on recent standards, like the 2022 ESC/ERS guidelines for pulmonary hypertension Limitations on the study and opportunities for future research For the latest studies from JHLT, visit www.jhltonline.org/current, or, if you're an ISHLT member, access your Journal membership at www.ishlt.org/jhlt.   Those on lung transplant teams should check the previous episode for a study on how rewarming ischemia time affects lung transplant outcomes.   Don't already get the Journal and want to read along? Join the International Society of Heart and Lung Transplantation at www.ishlt.org for a free subscription, or subscribe today at www.jhltonline.org.  

Intellistent Pioneering Innovation Transforming Treatment Strategies for Pediatric Pulmonary Arterial Hypertension and Dilated Cardiomyopathy

Dr Sandeep Sahay and Professor Franck Rahaghi discuss their Personal View on future treatment paradigms in pulmonary arterial hypertension.Read the full paper, Future treatment paradigms in pulmonary arterial hypertension: a personal view from physicians, health authorities, and patients, here: https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(24)00425-9/fulltextContinue this conversation on social!Follow us today at...https://twitter.com/thelancethttps://instagram.com/thelancetgrouphttps://facebook.com/thelancetmedicaljournalhttps://linkedIn.com/company/the-lancethttps://youtube.com/thelancettv

On this episode, we evaluate current guidelines and evidence-based treatment strategies for managing pulmonary arterial hypertension. We compare and contrast the efficacy, safety profiles, and appropriate use of targeted PAH therapies, adjunct treatments, and patient monitoring techniques.  Cole and I are happy to share that our listeners can claim ACPE-accredited continuing education for listening to this podcast episode! We have continued to partner with freeCE.com to provide listeners with the opportunity to claim 1-hour of continuing education credit for select episodes. For existing Unlimited (Gold) freeCE members, this CE option is included in your membership benefits at no additional cost! A password, which will be given at some point during this episode, is required to access the post-activity test. To earn credit for this episode, visit the following link below to go to freeCE's website: https://www.freece.com/ If you're not currently a freeCE member, we definitely suggest you explore all the benefits of their Unlimited Membership on their website and earn CE for listening to this podcast. Thanks for listening! If you want to support the podcast, check out our Patreon account. Subscribers will have access to all previous and new pharmacotherapy lectures as well as downloadable PowerPoint slides for each lecture. If you purchase an annual membership, you'll also get a free digital copy of High-Powered Medicine 3rd edition by Dr. Alex Poppen, PharmD. HPM is a book/website database of summaries for over 150 landmark clinical trials.You can visit our Patreon page at the website below:  www.patreon.com/corconsultrx We want to give a big thanks to Dr. Alex Poppen, PharmD and High-Powered Medicine for sponsoring the podcast..  You can get a copy of HPM at the links below:  Purchase a subscription or PDF copy - https://highpoweredmedicine.com/ Purchase the paperback and hardcover - Barnes and Noble website We want to say thank you to our sponsor, Pyrls. Try out their drug information app today. Visit the website below for a free trial: www.pyrls.com/corconsultrx We also want to thank our sponsor Freed AI. Freed is an AI scribe that listens, prepares your SOAP notes, and writes patient instructions. Charting is done before your patient walks out of the room. You can try 10 notes for free and after that it only costs $99/month. Visit the website below for more information: https://www.getfreed.ai/  If you have any questions for Cole or me, reach out to us via e-mail: Mike - mcorvino@corconsultrx.com Cole - cswanson@corconsultrx.com

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/MVM865. CME/AAPA/IPCE credit will be available until December 22, 2025.Managing Pulmonary Arterial Hypertension in the Era of Novel and Emerging Treatment Options: It Takes a Village In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc., Rahway, NJ, USA.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/MVM865. CME/AAPA/IPCE credit will be available until December 22, 2025.Managing Pulmonary Arterial Hypertension in the Era of Novel and Emerging Treatment Options: It Takes a Village In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc., Rahway, NJ, USA.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/MVM865. CME/AAPA/IPCE credit will be available until December 22, 2025.Managing Pulmonary Arterial Hypertension in the Era of Novel and Emerging Treatment Options: It Takes a Village In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc., Rahway, NJ, USA.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/MVM865. CME/AAPA/IPCE credit will be available until December 22, 2025.Managing Pulmonary Arterial Hypertension in the Era of Novel and Emerging Treatment Options: It Takes a Village In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc., Rahway, NJ, USA.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/MVM865. CME/AAPA/IPCE credit will be available until December 22, 2025.Managing Pulmonary Arterial Hypertension in the Era of Novel and Emerging Treatment Options: It Takes a Village In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc., Rahway, NJ, USA.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/MVM865. CME/AAPA/IPCE credit will be available until December 22, 2025.Managing Pulmonary Arterial Hypertension in the Era of Novel and Emerging Treatment Options: It Takes a Village In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc., Rahway, NJ, USA.Disclosure information is available at the beginning of the video presentation.

In this September 17, 2024 JACC issue, Dr. Zhi Jian Zhang and colleagues unveil a groundbreaking study on pulmonary arterial hypertension (PAH) that identifies plasma IgG fucosylation and glycan traits as promising prognostic markers. This research not only enhances survival predictions beyond current models but also opens intriguing possibilities for future therapeutic targets in PAH.

We're back with our Rapid Fire Journal Club, and talking about the NEJM 2023 STELLAR Trial of Sotatercept in Pulmonary Arterial Hypertension. This is a landmark trial that is actively changing the face of PAH treatment today. Listen to hear … Continue reading →

Johnson & Johnson Innovative Medicine, SFI CONNECT Centre for Future Networks & Communications (CONNECT), Maynooth University and Mater Misericordiae University Hospital has announced a new partnership to introduce an innovative health app. This application has been specifically developed using award-winning technology deployed by many UK-based hospitals and is designed to provide essential tools and information for patients living with pulmonary arterial hypertension (PAH), supporting improved health outcomes and quality of life right from their homes. The app also enables medical teams to educate patients about their condition and encourages proactive health management. PAH is a rare form of pulmonary hypertension, which is high blood pressure in the lungs with an annual incidence rate of 3.11 patients per million of the total population of Ireland. Symptoms of PAH include: breathlessness, particularly during physical activity; fatigue; dizziness; syncope (fainting or passing out); peripheral oedema (swelling to lower legs or hands) and chest pain. These symptoms can severely impact a patient's ability to carry out normal daily activities. As the disease progresses, some patients may experience constant dyspnoea (shortness of breath or breathlessness) and fatigue so that even simple tasks, such as getting dressed and walking short distances, become difficult which can severely impact a patient's quality of life.3 The Mater Hospital is the National Centre of Excellence for PAH and is attended by patients from across Ireland. The initial rollout of the app will benefit up to 250 people living with the rare disease who attend the Mater Misericordiae University Hospital for treatment, empowering them to manage their disease more effectively, from their homes. The app's integration into the patients' care routine is expected to: Improve the quality of life of patients, empowering them to self-manage elements of their condition through access to credible and localised information about the management of their condition, their treatment pathways and online support services. Improve medication adherence by providing patients with medication support and education. Reduce hospital appointments by providing patients with self-management information and the use of a health tracker to enable patient-initiated reviews. This would positively impact patients who are not located close to the hospital, to reduce the burden of travel, parking and support from loved ones. Provide holistic guidance and education to patients on their emotional, physical and nutritional wellbeing with the aim of improving their quality of life. Improve the quality of care through personalised, up-to-date medical advice from trusted clinical teams as well as deploying remote education for healthcare professionals through the app. Enhance the experience of healthcare professionals by streamlining patient interactions and reducing administrative burdens, creating greater efficiencies that benefit both the professionals, and the patient. This partnership brings together the expertise and resources of Johnson & Johnson Innovative Medicine, formerly known as Janssen, alongside Maynooth University, CONNECT and the Mater Misericordiae University Hospital to offer innovative support for patients. It underscores the commitment of both public, private and academic sectors to enhance patient care, improve quality of life, and address the increasing demands on the Irish healthcare system, serving as a national pathway personalised to local clinical and system needs. A presentation about the new app will be made today at the International Digital Health Summer School 2024, hosted at the Innovation Value Institute, Maynooth University. Developed by Health and Care Innovations (HCI), the CONNECTPlus app has been designed in collaboration with nurses, clinicians and PAH patients, to ensure it closely supports the local pathways of care, patient needs and challenges faced by peo...

On this episode of JHLT: The Podcast, the JHLT Digital Media Editors explore two studies from the June issue of The Journal of Heart and Lung Transplantation. Digital Media Editor Van-Khue Ton, MD, a transplant cardiologist from Massachusetts General Hospital, hosts this episode.   First, Dr. Ton and Digital Media Editor Marty Tam, MD, interview their first guests, first author Matthew Carey, MD, MBA, and senior author Justin Fried, MD, both of the Columbia University Irving Medical Center in New York City, on their study “Aortic Root Thrombosis in patients with HeartMate 3 left ventricular assist device support.”   This retrospective study of all patients receiving a HeartMate 3 LVAD at a single center between November 2014 and August 2020. The study evaluated findings related to patients with aortic root thrombosis, classified as having at least 1 echocardiogram or contrast-enhanced CT scan with thrombus. In the population of 197 patients, 19 had aortic root thrombus, which was ultimately associated with an increased risk of developing significant aortic regurgitation during the study period.   Drs. Carey and Fried discuss whether aortic valve opening is associated with increased risk of aortic root thrombus, how to balance the bleeding-thrombosis scale in patients, and how the study fits in the context of prior generations of LVAD.   Next, Dr. Ton joins and Digital Media Editor Erika Lease, MD, FCCP, to interview, Jacqueline DesJardin, MD, a Fellow in the department of medicine at the University of California San Francisco. Dr. DesJardin is first author on the study “Investigating the “sex paradox” in pulmonary arterial hypertension: Results from the Pulmonary Hypertension Association Registry (PHAR).”   PHAR is a multicenter US-based registry of patients with PAH, and this study analyzed 1,891 patients from the registry, 1,425 (75%) of whom were female. At baseline, compared to men, women had worse functional status and worse hemodynamics. Women were more likely to be on triple therapy or parenteral prostacyclin therapies at baseline. Interestingly, women had better survival than men, even after adjusting for numerous variables.   In the discussion, Dr. DesJardin explains what collider stratification bias is, and how it may illuminate the complex epidemiological system that creates this disparity. She shares the three potential causal models posed in the study, and considers how the study might be followed up.   Follow along at www.jhltonline.org/current, or, if you're an ISHLT member, access your Journal membership at www.ishlt.org/jhlt.   Don't already get the Journal and want to read along? Join the International Society of Heart and Lung Transplantation at www.ishlt.org for a free subscription, or subscribe today at www.jhltonline.org.    

Drs. Meghan Cirulis and Katherine Cox-Flaherty discuss key issues surrounding reproductive health in pulmonary hypertension with two national experts on the subject: Dr Anna Hemnes and Dr. Elizabeth Sonntag.

This week, please join author Stephan Rosenkranz, Editorialist Lewis Rubin, and Associate Editor Kelly Chin as they discuss the article "Positive Vasoreactivity Testing in Pulmonary Arterial Hypertension: Therapeutic Consequences, Treatment Patterns, and Outcomes in the Modern Management Era" and the Editorial "Is There a Role for Calcium Channel Blockers in the Contemporary Treatment Paradigm for Pulmonary Arterial Hypertension?" For the episode transcript, visit:  https://www.ahajournals.org/do/10.1161/podcast.20240510.641533

EIn this episode of Take a Pain Check, host Natasha introduces Emily Wahl, who bravely shares her journey living with Juvenile Rheumatoid Arthritis (JRA), Sjogren's syndrome, Lupus, Pulmonary Arterial Hypertension, and FSGS. Emily candidly discusses her diagnosis story, recounting childhood experiences with arthritis and the challenges of managing various medications. She reflects on how her health conditions influenced her career choices and relationships, especially during pregnancy. Emily advocates for patients like herself, emphasizing the importance of a supportive care team and sharing coping strategies for the emotional weight of new diagnoses. Additionally, she offers insights into navigating pregnancy with chronic illnesses and provides valuable advice for managing multiple conditions effectively. Join our peer support group here for this month's session in May: https://us02web.zoom.us/meeting/register/tZ0tdemsrj8oHtwosUn8w7ZcwHxdGYZPDEDv#/registration Emily's socials: @healmewholeheartedly www.healmewholeheartedly.com Our socials: Website: ⁠https://www.takeapaincheck.com/⁠ Instagram: ⁠ https://www.instagram.com/takeapaincheck_/ Tiktok: ⁠https://www.tiktok.com/@takeapaincheck?lang=en Facebook: https://www.facebook.com/TakeaPainCheck/ LinkedIn: https://www.linkedin.com/company/take-a-pain-check/?originalSubdomain=ca

CME credits: 1.00 Valid until: 19-11-2024 Claim your CME credit at https://reachmd.com/programs/cme/pulmonary-arterial-hypertension-screening-diagnosis-and-optimizing-management/24048/ Learn how to use guideline recommendations to establish a diagnosis of pulmonary arterial hypertension (PAH), develop evidence-based individualized treatment plans, and explore innovative therapies under investigation for PAH management. Hear from expert faculty on how to integrate the patient's perspective when personalizing management plans for PAH.=

Commentary by Dr. Candice Silversides

Drs Michelle Kittleson and Ronald Oudiz dive into everything cardiologists need to know about the diagnosis and treatment of pulmonary hypertension. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/997320). The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals. Resources Heart Failure https://emedicine.medscape.com/article/163062-overview Pulmonary Arterial Hypertension https://emedicine.medscape.com/article/303098-overview Cardiac Catheterization in Pulmonary Hypertension: Doing It Right, With a Catheter on the Left https://pubmed.ncbi.nlm.nih.gov/33224785/ How to Initiate and Uptitrate GDMT in Heart Failure: Practical Stepwise Approach to Optimization of GDMT https://pubmed.ncbi.nlm.nih.gov/36456074/ Phosphodiesterase Inhibitors https://www.ncbi.nlm.nih.gov/books/NBK559276/ Cardiovascular Biology of Prostanoids and Drug Discovery https://pubmed.ncbi.nlm.nih.gov/32295420/ Soluble Guanylate Cyclase as an Emerging Therapeutic Target in Cardiopulmonary Disease https://pubmed.ncbi.nlm.nih.gov/21606405/ Pulmonary Hypertension Association https://phassociation.org/

CME credits: 4.75 Valid until: 30-11-2024 Claim your CME credit at https://reachmd.com/programs/cme/pulmonary-arterial-hypertension-and-connective-tissue-disease/16512/ The Midwest Regional Pulmonary Hypertension Summit occurred on October 14, 2023, in Chicago, IL. The event highlighted the management of PH with other coexisting comorbidities. Leading experts discussed the appropriate risk stratification, management of PH, updates on ERS/ERC guidelines, and optimal patient care practice.

Commentary by Dr. Valentin Fuster

It's pulmonary hypertension month on JHLT: The Podcast! The JHLT Digital Media Editors explore two PVD-related manuscripts from the November issue of The Journal of Heart and Lung Transplantation. Digital Media Editor Marty Tam, MD, assistant professor in the division of cardiovascular medicine at the University of Michigan, hosts this episode.   First, hear from first author Zvonimir Rako, MD, on his team's study “Clinical and functional relevance of right ventricular contraction patterns in pulmonary hypertension.”   The right ventricle (RV) has a complex contraction pattern. For patients with pulmonary hypertension (PH), right ventricular to pulmonary artery (RV-PA) coupling is important when considering how the RV responds to increases in afterload. Uncoupling occurs with progressive disease and the degree of uncoupling can be derived from pressure–volume loop analysis as the ratio between end-systolic and arterial elastance (Ees/Ea).   In this exploratory analysis of the prospective EXERTION study, the authors determined the relationship between RV contraction patterns and RV-PA coupling in patients with PH. They also correlated RV contraction patterns to hemodynamic risk profiles. For details on what the study found about how PH programs can use the results in their practice, listen to the discussion in the episode.   Next, the editors explored the study “Impact of sex on outcome after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.” The podcast hosted first author Justin C.Y. Chan, MD, MPhil and senior author Marc de Perrot,  MD, MSc, FRCSC.   The impact of sex on long-term outcomes after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension (CTEPH) has remained unclear. The authors of this study sought to evaluate the early and long-term outcomes after pulmonary endarterectomy to see if sex had an impact on the risk of residual pulmonary hypertension and need for targeted PH medical therapy.    For details on what this retrospective single-center study found, including the mechanics of sex differences and the potential changes to clinical approach, check out the episode.   Follow along at www.jhltonline.org/current, or, if you're an ISHLT member, log in at ishlt.org/journal-of-heart-lung-transplantation.  Don't already get the Journal and want to read along? Join the International Society of Heart and Lung Transplantation at www.ishlt.org for a free subscription, or subscribe today at www.jhltonline.org.

CME credits: 4.25 Valid until: 31-10-2024 Claim your CME credit at https://reachmd.com/programs/cme/video-demo-cardiopulmonary-exercise-testing-in-pulmonary-arterial-hypertension-part-2/16332/ This year's West Regional PH Summit occurred on September 9, 2023, in Los Angeles, CA. Over a dozen regional faculty presented key topics impacting clinical practice and PH patient outcomes. The following topics were discussed at the event: Important advancements and updates across the PH disease spectrum The latest ERS/ESC guidelines for diagnosing and treating PH Critical advancements in screening, diagnosis, and treatment of CTEPH/CTED, lung disease-associated PAH, and CTD-associated PAH Real-world examples and data related to all discussion topics

CME credits: 4.25 Valid until: 31-10-2024 Claim your CME credit at https://reachmd.com/programs/cme/video-demo-cardiopulmonary-exercise-testing-in-pulmonary-arterial-hypertension-part-1/16331/ This year's West Regional PH Summit occurred on September 9, 2023, in Los Angeles, CA. Over a dozen regional faculty presented key topics impacting clinical practice and PH patient outcomes. The following topics were discussed at the event: Important advancements and updates across the PH disease spectrum The latest ERS/ESC guidelines for diagnosing and treating PH Critical advancements in screening, diagnosis, and treatment of CTEPH/CTED, lung disease-associated PAH, and CTD-associated PAH Real-world examples and data related to all discussion topics

The CardioNerds and Pulm PEEPs have joined forces to co-produce this important episode, delving into the management of decompensated right ventricular failure in pulmonary arterial hypertension. Joining us for this informative discussion are Pulm PEEPs co-founders, Dr. David Furfaro and Dr. Kristina Montemayor, along with Dr. Leonid Mirson (Internal Medicine Resident at Johns Hopkins Osler Medical Residency and Associate Editor of Pulm PEEPs), Dr. Bavya Varma (Internal Medicine Resident at Johns Hopkins, rising Cardiology Fellow at NYU, and CardioNerds Academy graduate), Dr. Mardi Gomberg-Maitland (Medical Director of the Pulmonary Hypertension Program at George Washington Hospital), and Dr. Rachel Damico (Pulmonologist and Associate Professor of Medicine at Johns Hopkins Hospital). Audio editing by CardioNerds Academy Intern, student doctor Adriana Mares. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. CardioNerds Heart Success Series PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Show notes - Decompensated Right Ventricular Failure in Pulmonary Arterial Hypertension A 21-year-old woman with a past medical history notable for congenital heart disease (primum ASD and sinus venosus with multiple surgeries) complicated by severe PAH on home oxygen, sildenafil, ambrisentan, and subcutaneous treprostinil is presenting with palpitations, chest pain, and syncope. She presented as a transfer from an outside ED where she arrived in an unknown tachyarrhythmia and had undergone DCCV due to tachycardia into the 200s and hypotension. On arrival at our hospital, she denied SOB but did endorse nausea, leg swelling, and poor medication adherence. Her initial vitals were notable for a BP of 80/50, HR 110, RR 25, and saturating 91% on 5L O2.  On exam, she was uncomfortable appearing but mentating well. She had cool extremities with 1-2+ LE edema. Her JVP was 15cm H2O. She has an RV Heave and 2/6 systolic murmur. Her lungs were clear bilaterally. Her labs were notable for Cr 2.0, an anion gap metabolic acidosis (HCO3 = 11), elevated lactate (4.1), elevated troponin to 14,  and a pro-BNP of ~5000.  Her CBC was unremarkable. Her EKG demonstrated 2:1 atrial flutter at a rate of 130. Diagnosing RV failure in patients with PH: RV dysfunction and RV failure are two separate entities. RV dysfunction can be measured on echocardiography, but RV failure can be thought of as a clinical syndrome where there is evidence of RV dysfunction and elevated right sided filling pressures. RV failure is a spectrum and can present with a range of manifestations from evidence of R sided volume overload and markers of organ dysfunction, all the way to frank cardiogenic shock. Most patients with RV failure are not in overt shock. One of the first signs of impending shock in patients with RV failure is the development of new or worsening hypoxemia. Patients with decompensated RV failure approaching shock often do not present with symptoms classic for LV low flow state. Instead, hypoxia 2/2 VQ mismatching may be the first sign and they can be otherwise well appearing. Particularly because patients with PH tend to be younger, they can often appear compensated until they rapidly decompensate. Causes of decompensation for patients with RV dysfunction and PH: Iatrogenesis (inadvertent cessation of pulmonary vasodilators by providers, surgery if providers are not familiar with risks of anesthesia), non-adherence to pulmonary vasodilators (either due to affordability issues or other reasons), infections, arrhythmias (particularly atrial arrhythmias), and progression of underlying disease. Patients with atrial arrhythmias (atrial flutter or atrial fibrillation) and pulmonary hypertension do not tolerate the loss of...

We are extremely excited to be hosting this episode in collaboration with CardioNerds! We have known Amit and Dan for many years, and they have been huge supporters of Pulm PEEPs, so it is an honor to address a topic … Continue reading →

El podcast de JHLTenEspañol: presentamos por primera vez un podcast de JHLT en Español, conducido por Marta Farrero, MD, PhD, en el que repasamos 4 artículos destacados de 2022, cada uno centrado en el foco de interés de las redes interdisciplinarias de ISHLT. El artículo sobre soporte circulatorio se titula “La recuperación de la función ventricular se asocia con mejores resultados en asistencia ventricular”, con Cameron Olsen, MD, como primer firmante, y es comentado por el Sebastián Rojas, MD. Se analiza el impacto clínico favorable de la recuperación de la fracción de eyección por encima del 40% en una cohorte retrospectiva de pacientes con implante de asistencia ventricular de larga duración. El artículo sobre trasplante pulmonar se titula “Síndrome del injerto restrictivo vs bronquiolitis obliterante: caracterización inmunológica y molecular de exosomas circulantes”, con Sandhya Bansal, PhD primer firmante, comentado por Alejandro Bertolotti, MD. Este trabajo se propone tratar de caracterizar la patogenia del rechazo crónico analizando el contenido de moléculas proinflamatorias y potencialmente inmunogénicas contenidas en exosomas aislados del plasma de receptore de trasplante pulmonar. El artículo sobre hipertensión pulmonar se titula “Escalas de riesgo y predicción clínica en hipertensión arterial pulmonar, un análisis del freedom-EV” con de Raymond L. Benza, MD como primer firmante y Roberto Bernardo, MD, MS para realizar los comentarios. En este subanálisis se observa como las escalas de riesgo de los pacientes con hipertensión pulmonar mejoran tras la administración de treprostinil oral. El cuarto y último artículo se titula “MicroRNA circulante y rechazo mediado por anticuerpos en el trasplante cardíaco”, con Palak Shah, MD, MS como primer firmante y comentado por Vanessa Blumer, MD. En este trabajo se identificó qué microRNA se asocian a rechazo celular y mediado por anticuerpos, permitiendo hacer el diagnóstico con una buena sensibilidad y especificidad.

CME credits: 1.25 Valid until: 27-03-2024 Claim your CME credit at https://reachmd.com/programs/cme/efficacy-and-safety-of-macitentan-tadalafil-fixed-dose-combination-in-pulmonary-arterial-hypertension-results-from-the-randomized-controlled-phase-iii-a-due-study/15284/ In this program, expert faculty discuss data presented at the 2023 ACC Congress in a concise, informative, on-demand format. This format extends the congress analysis to a broader audience with greater detail than what is available in abstracts. Rapid advances from the meeting require well-planned educational programming to bridge knowledge, competence, and performance gaps.

CME credits: 1.25 Valid until: 27-03-2024 Claim your CME credit at https://reachmd.com/programs/cme/the-stellar-phase-3-trial-a-study-of-sotatercept-in-combination-with-background-therapy-for-the-treatment-of-pulmonary-arterial-hypertension/15282/ In this program, expert faculty discuss data presented at the 2023 ACC Congress in a concise, informative, on-demand format. This format extends the congress analysis to a broader audience with greater detail than what is available in abstracts. Rapid advances from the meeting require well-planned educational programming to bridge knowledge, competence, and performance gaps.

ACC Recap No. 2: Pacing in HFpEF, Oral PCSK9 inhibitor, PAH, soft thinking on adherence, and so called metabolically healthy obese are discussed by John Mandrola, MD, in this week's podcast. This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I. Pacing in HFpEF No Exercise Boost From Pacemaker in HFpEF With Impaired HR Response: RAPID-HF https://www.medscape.com/viewarticle/989681 - Rate-Adaptive Atrial Pacing for Heart Failure With Preserved Ejection FractionThe RAPID-HF Randomized Clinical Trial https://jamanetwork.com/journals/jama/article-abstract/2802147 - Accelerated Pacing a Possible Strategy for Preserved-EF Heart Failure? https://www.medscape.com/viewarticle/987815 - Could a Breakthrough in Heart Failure With Preserved Ejection Fraction Just Take a Change of Pace? - https://www.medscape.com/viewarticle/988088 - Effect of Personalized Accelerated Pacing on Quality of Life, Physical Activity, and Atrial Fibrillation in Patients With Preclinical and Overt Heart Failure With Preserved Ejection Fraction: The myPACE Randomized Clinical Trial https://jamanetwork.com/journals/jamacardiology/fullarticle/2801001 - Effect of β-Blocker Withdrawal on Functional Capacity in Heart Failure and Preserved Ejection Fraction https://doi.org/10.1016/j.jacc.2021.08.073 II Oral PCSK9i Oral PCSK9 Inhibitor Shows Encouraging LDL Lowering https://www.medscape.com/viewarticle/989655 - Efficacy and safety of the oral PCSK9 inhibitor MK-0616: a phase 2b randomized controlled trial https://www.jacc.org/doi/10.1016/j.jacc.2023.02.018 III PAH 'Unheard of' PAH Improvement With Novel Drug: STELLAR https://www.medscape.com/viewarticle/989612 - Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension https://www.nejm.org/doi/full/10.1056/NEJMoa2213558 IV Medical Adherence Waiving Co-Pays for CV Meds as Adherence Incentive Doesn't Cut Clinical Risk: ACCESS Trial https://www.medscape.com/viewarticle/989474 - Eliminating Medication Copayments for Low-income Older Adults at High Cardiovascular Risk: A Randomized Controlled Trial https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.064188 - Medicaid Expansion: Good First Step, but No Panacea for CV Care https://www.medscape.com/viewarticle/975141 - Health Care Access and Management of Cardiovascular Risk Factors Among Working-Age Adults With Low Income by State Medicaid Expansion Status https://jamanetwork.com/journals/jamacardiology/article-abstract/2793120 - Rand Link https://www.rand.org/pubs/reports/R3055.html - The Oregon Health Insurance Experiment https://www.healthaffairs.org/do/10.1377/hpb20150716.236899/full/ - Effect of Health Insurance in India: A Randomized Controlled Trial https://www.nber.org/papers/w29576 - Full Coverage for Preventive Medications after Myocardial Infarction https://www.nejm.org/doi/full/10.1056/nejmsa1107913 - Effect of Medication Co-payment Vouchers on P2Y12 Inhibitor Use and Major Adverse Cardiovascular Events Among Patients With Myocardial InfarctionThe ARTEMIS Randomized Clinical Trial https://jamanetwork.com/journals/jama/fullarticle/2720024 - Coronary CT Angiography and 5-Year Risk of Myocardial Infarction https://www.nejm.org/doi/full/10.1056/NEJMoa1805971 IV Metabolically Healthy Obese 'Metabolically Healthy Obesity' Rising, but Still Uncommon https://www.medscape.com/viewarticle/989398 - Trends in the Prevalence of Metabolically Healthy Obesity Among US Adults, 1999-2018 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2802164 You may also like: Medscape editor-in-chief Eric Topol, MD, and master storyteller and clinician Abraham Verghese, MD, on Medicine and the Machine https://www.medscape.com/features/public/machine The Bob Harrington Show with Stanford University Chair of Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

This month's JHLT: The Podcast is hosted by Digital Media Editor David Schibilsky, MD, who leads a discussion of two studies from the March issue of The Journal of Heart and Lung Transplantation—and the first authors who presented them.   First, the editors explore a study entitled “Angiopoietin 2 and hsCRP are associated with pulmonary hemodynamics and long-term mortality respectively in CTEPH—Results from a prospective discovery and validation biomarker study,” which comes from Hadinnapola and colleagues at the Papworth group in Cambridge, UK.   The editors welcome Charaka Hadinnapola, MA, MB, BChir, first author on the CTEPH study, to share the rationale in performing the research, its main findings, the changing understanding of the pathobiology of pulmonary arterial hypertension, and how Ang2 and hsCRP fit into the bigger cytokine picture in CTEPD and CTEPH patients.   Next, the editors welcome author J.K. Peel, MD, MSc, from the University of Toronto to discuss the paper her first authored, “Determining the impact of ex-vivo lung perfusion on hospital costs for lung transplantation: a retrospective cohort study.”   This retrospective, before-after, propensity-score weighted cohort study explores how EVLP affects hospital costs and the associated transplant procedures, intending to evaluate whether the benefits of EVLP offset its additional cost. Dr. Peel shares what changes occurred at his center during the study period, how the results compare to other published evidence on EVLP costs, and whether the results are transferable to smaller centers.   Follow along at www.jhltonline.org/current, or, if you're an ISHLT member, log in at ishlt.org/journal-of-heart-lung-transplantation.  Don't already get the Journal and want to read along? Join the International Society of Heart and Lung Transplantation at www.ishlt.org for a free subscription, or subscribe today at www.jhltonline.org.    

Lisa Yanez is the CEO of Aerami Therapeutics, a clinical stage biopharmaceutical company focused on the rare cardiopulmonary disease pulmonary arterial hypertension. Early studies show that using this smart breath-activated inhalation delivery system to administer AER901, inhaled Imatinib reduces side effects and requires less frequent administration by those suffering from PAH. Lisa explains, "Our company is focused on a rare disease, pulmonary arterial hypertension. There was a drug that was an oral drug that was studied before, but due to the side effects, that trial ceased. That said, if you look at the efficacy of that drug, it was one of the best-performing drugs ever for these patients. It didn't just help with symptoms. It also helped the underlying cause of the disease. What our company has decided to do is take a very intelligent inhaled patient-proven device and couple it with this product to generate the best of both worlds. What we're trying to do is helping patients live longer, but our mission is also helping patients live better." "One of the reasons I've fallen in love with this particular condition is because it mostly impacts women of childbearing age. They go about two years not knowing what's wrong with them. They have shortness of breath, they have a lot of fatigue, they're very dizzy, and sometimes they pass out. They go to all these different doctors, and typically it does take two years, and people think they're crazy." "Then, once they're diagnosed, there are 15 approved therapies. Even then, there's only a five to seven-year time span in terms of survival. And so, there's a lot more that needs to be done with these particular patients." @AeramiTx #Aerami #Cardiopulmonary #RareDisease #PulmonaryArterialHypertension #PulmonaryHypertension #PAH #PH #HeartDisease #LungDisease #AER901 #InhaledTherapeutics #AER601 aerami.com Listen to the podcast here

Lisa Yanez is the CEO of Aerami Therapeutics, a clinical stage biopharmaceutical company focused on the rare cardiopulmonary disease pulmonary arterial hypertension. Early studies show that using this smart breath-activated inhalation delivery system to administer AER901, inhaled Imatinib reduces side effects and requires less frequent administration by those suffering from PAH. Lisa explains, "Our company is focused on a rare disease, pulmonary arterial hypertension. There was a drug that was an oral drug that was studied before, but due to the side effects, that trial ceased. That said, if you look at the efficacy of that drug, it was one of the best-performing drugs ever for these patients. It didn't just help with symptoms. It also helped the underlying cause of the disease. What our company has decided to do is take a very intelligent inhaled patient-proven device and couple it with this product to generate the best of both worlds. What we're trying to do is helping patients live longer, but our mission is also helping patients live better." "One of the reasons I've fallen in love with this particular condition is because it mostly impacts women of childbearing age. They go about two years not knowing what's wrong with them. They have shortness of breath, they have a lot of fatigue, they're very dizzy, and sometimes they pass out. They go to all these different doctors, and typically it does take two years, and people think they're crazy." "Then, once they're diagnosed, there are 15 approved therapies. Even then, there's only a five to seven-year time span in terms of survival. And so, there's a lot more that needs to be done with these particular patients." @AeramiTx #Aerami #Cardiopulmonary #RareDisease #PulmonaryArterialHypertension #PulmonaryHypertension #PAH #PH #HeartDisease #LungDisease #AER901 #InhaledTherapeutics #AER601  aerami.com Download the transcript here

This month on Episode 45 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the February 3rd and February 17th issues of Circulation Research. This episode also features an interview with Dr Hind Lal and Dr Tousif Sultan from the University of Alabama at Birmingham about their study Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation.   Article highlights:   Pi, et al. Metabolomic Signatures in PAH   Carnevale, et al. Thrombosis TLR4-Mediated in SARS-CoV-2 Infection   Cai, et al. Macrophage ADAR1 in AAA   Koide, et al. sEVs Accelerate Vascular Calcification in CKD   Cindy St. Hilaire:        Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cynthia St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to be highlighting the articles from our February 3rd and 17th issues of Circulation Research. I'm also going to have a chat with Dr Hind Lal and Dr Tousif Sultan from the University of Alabama at Birmingham about their study, Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation. But before I get to the interviews, here are a few article highlights.   Cindy St. Hilaire:        The first article I want to highlight comes from the laboratory of Dr Peter Leary at the University of Washington, and the title is Metabolomic Signatures Associated With Pulmonary Arterial Hypertension Outcomes. Pulmonary Arterial Hypertension or PAH is a rare but life-threatening disease in which progressive thickening of the walls of the lung's blood vessels causes increased blood pressure and that increased blood pressure ultimately damages the heart's right ventricle.   Interestingly, progression to heart failure varies considerably among patients, but the reasons why there is variability are not well understood. To find out, this group turned their attention to patient metabolomes, which differ significantly from those of healthy people and thus may also change with severity. Blood samples from 117 PAH patients were analyzed for more than a thousand metabolites by mass spectrometry and the patient's progress was followed for the next three years. 22 patients died within a three-year period and 27 developed significant right ventricle dilation. Other measures of severity included pulmonary vascular resistance, exercise capacity and levels of BNP, which is a metric of heart health. Two metabolic pathways, those relating to polyamine and histidine metabolism, were found to be linked with all measures of severity suggesting a key role for them in disease pathology. While determining how these pathways influence disease as a subject for further study, the current findings may nevertheless lead to new prognostic indicators to inform patient care.   Cindy St. Hilaire:        The next article I want to discuss is coming from our February 3rd issue of Circulation Research and this is coming from the laboratory of Dr Francisco Violi at the University of Rome and the title is Toll-Like Receptor 4-Dependent Platelet-Related Thrombosis in SARS-CoV-2 Infection. Thrombosis can be a complication of COVID-19 and it is associated with poor outcomes, including death. However, the exact mechanism by which the virus activates platelets, which are the cells that drive thrombosis, is not clear. For one thing, platelets do not appear to express the receptor for SARS-CoV-2. They do however, express the TLR4 receptor and that's a receptor that mediates entry of other viruses as part of the immune response. And TLR4 is ramped up in COVID-19 patient platelets. This group now confirms that, indeed, SARS-CoV-2 interacts with TLR4, which in turn triggers thrombosis.   The team analyzed platelets from 25 patients and 10 healthy controls and they found that the platelet activation and thrombic activity were both boosted in the patient samples and could not be blocked using a TLR4 inhibitor. Additionally, immunoprecipitation and immunofluorescent experiments further revealed colocalization between the virus protein and the TLR4 receptor on patient platelets. The team went on to show that the signaling pathway involved reactive oxygen species producing factors p47phox and Nox2, and that inhibition of phox 47, like that of the TLR4 receptor itsel,f could prevent platelet activation. As such, this study suggests that inhibiting either of these proteins may form the basis of an antithrombotic treatment for COVID-19.   Cindy St. Hilaire:        The third article I want to highlight is coming from the lab of Shi-You Chen at University of Missouri and the title of this article is ADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic Aneurysm. Macrophage activation plays a critical role in abdominal aortic aneurysm development, or AAA development. Inflammation is a component of this pathology; however, the mechanisms controlling macrophage activation and vascular inflammation in AAA are largely unknown. The ADAR1 enzyme catalyzes the conversion of adenosine to inosine in RNA molecules and thus this conversion can serve as a rheostat to regulate RNA structure or the gene coding sequence of proteins. Several studies have explored the role of ADAR1 in inflammation, but its precise contribution is not fully understood, so the objective of this group was to study the role of ADAR1 in macrophage activation and AAA formation.   Aortic transplantation was conducted to determine the importance of nonvascular ADAR1 in AAA development and dissection and angiotensin II infusion of ApoE knockout mice combined with a macrophage specific knockout of ADAR1 was used to study the role of ADAR1 macrophage specific contributions to AAA formation and dissection. Allograft transplantation of wild type abdominal aortas to ADAR1 haploinsufficient recipient mice significantly attenuated AAA formation. ADAR1 deficiency in hematopoietic stem cells also decreased the prevalence and the severity of AAA and it also inhibited macrophage infiltration into the aortic wall. ADAR1 deletion blocked the classic macrophage activation pathway. It diminished NF-κB signaling and it enhanced the expression of a number of anti-inflammatory microRNAs. Reconstitution of ADAR1 deficient but not wild type human monocytes to immunodeficient mice blocked the aneurysm formation in transplanted human arteries. Together these results suggest that macrophage ADAR1 promotes aneurysm formation in both mouse and human arteries through a novel mechanism of editing the microRNAs that target NF-κB signaling, which ultimately promotes vascular inflammation in AAA.     Cindy St. Hilaire:        The last article I want to highlight is also from our February 17th issue of Circulation Research and it is coming from the lab of Shintaro Mandai at Tokyo Medical and Dental University and the title of the article is Circulating Extracellular Vesicle Propagated MicroRNA signatures as a Vascular Calcification Factor in Chronic Kidney Disease. Chronic Kidney Disease or CKD accelerates vascular calcification in part by promoting the phenotypic switching of vascular smooth muscle cells to osteoblast like cells. This study investigated the role of circulating small extracellular vesicles or SUVs from the kidneys in promoting this osteogenic switch. CKD was induced in rats and in mice by an adenine induced tubular interstitial fibrosis and serum from these animals induced calcification in in vitro cultures of A-10 embryonic rat smooth muscle cells. Intraperitoneal administration of a compound that prevents SEV biosynthesis and release inhibited thoracic aortic calcification in CKD mice under a high phosphorus diet. In Chronic Kidney Disease, the microRNA transcriptome of SUVs revealed a depletion of four microRNAs and the expression of the microRNAs inversely correlated with kidney function in CKD patients.   In vitro studies found that transected microRNA mimics prevented smooth muscle cell calcification in vitro. In silico analyses revealed that VEGF-A was a convergent target of all four microRNAs and leveraging this, the group used in vitro and in vivo models of calcification to show the inhibition of the VEGF-A, VEGFR-2 signaling pathway mitigated calcification. So in addition to identifying a new potential therapeutic target, these SUV propagated microRNAs are a potential biomarker that can be used for screening patients to determine the severity of CKD and possibly even vascular calcification.   Cindy St. Hilaire:        Today I have with me Dr Hind Lal who's an associate professor of medicine at the University of Alabama Birmingham and his post-doctoral fellow and the lead author of the study Dr Tousif Sultan. And their manuscript is titled Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation. And this article is in our February 3rd issue of Circulation Research. So thank you both so much for joining me today.   Tousif Sultan:              Thank you.   Hind Lal:                     Thank you for taking time.   Cindy St. Hilaire:        So ponatinib, it's a tyrosine kinase inhibitor and from my understanding it's the only treatment option for a specific group of patients who have chronic myelogenous leukemia and they have to harbor a specific mutation. And while this drug helps to keep these patients alive essentially, it's extremely cardiotoxic. So cardiotoxicity is somewhat of a new field. So Dr Lal, I was wondering how did you get into this line of research?    Hind Lal:                    So I was fortunate enough to be in the lab of Dr Tom Force and he was kind of father of this new area, now is very developed, it's called cardio-oncology. On those days there were basically everything started in cardio-oncology. So I just recall the first tyrosine kinase approved by FDA was in 2000 and that was... Imagine and our paper came in Nature Medicine 2005 and discovering there is... so to elaborate it a little bit, the cancer therapy broadly divided in two parts. One is called non-targeted therapy like chemotherapy, radiations, et cetera, and then there are cytotoxic drugs. So those cytotoxic drugs because they do not have any targeted name on it so they are, cardiotoxic are toxic to any organ was very obvious and understanding. When these targeted therapy came, which is mainly kinase inhibitor are monoclonal antibodies. So these are targeted to a specific pathway that is activated only in the cancer cells but not in any other cells in the body so they were proposed as like magic bullets that can take off the cancer without any cardiotoxity or minimal side effects. But even in the early phase like 2005 to 2010, these came out, these so-called targeted, they are not very targeted and they are not also the magic bullets and they have serious cardiotoxicity.   Cindy St. Hilaire:        And so what's the mechanism of action of ponatinib in the leukemia and how does that intersect with the cardiovascular system?   Hind Lal:                     Yeah, so this is very good question I must say. So what we believe at this point because, so leukemia if you know is driven by the famous Philadelphia chromosome, which is a translicational gene, one part of human chromosome nine and one part of human chromosome 22 and they translocate make a new gene which is BCR-ABL gene. And because it was discovered in Philadelphia UPENN, is named that Philadelphia chromosome, which is very established mechanism, that's how CML is driven. But what we have discovered that the cardiotoxicity driven by totally, totally different from the ponatinib is one of the inflammatory So it's kind of goodening. So this question is so good. One kind of toxicity is called on-target, when toxicity is mediated by the same mechanism, what is the mechanism of the drug to cure the cancer? So in that case your absolute is minimal because if you manipulate that, the drug's ability to cure the cancer will be affected but if the toxicity and the efficacy is driven by two different mechanism, then as in case of ponatinib seems like it's NLRP3 and inflammasome related mechanism. So this can be managed by manipulating this pathway without hampering the drug efficacy on the cancer.   Cindy St. Hilaire:        So what exactly is cardiotoxicity and how does it present itself in these patients?   Hind Lal:                     So these drugs like ponatinib, they call broader CVD effects. So it's not just cardiac, so they also in hypertensives and atherosclerosis and thrombosis, those kind of thing. But our lab is primarily focused on the heart. So that's why in this paper we have given impresses on the heart. So what we believe at this point that ponatinib lead to this proinflammatory pathway described in this paper, which is just 108A9-NLRP3-IL-1β and this inflammatory pathway lead to a cytokine storm very much like in the COVID-19 and these cytokine storms lead to excessive myocarditis and then finally cardiac dysfunction.   Cindy St. Hilaire:        Is the cytokine storm just local in the cardiac tissue or is it also systemic in the patients? Is cardiotoxicity localized only or is it a more systemic problem?   Tousif Sultan:              I would like to add in this paper we have included that we look this cytokine things and explain blood circulation, bone marrow. So the effect is everywhere, it's not local. So we didn't check other organs, maybe other organs also being affected with the ponatinib treatment.   Cindy St. Hilaire:        And what's the initial phenotype of a patient has when they start to get cardiotoxicity, what's kind of like a telltale symptom?   Hind Lal:                     So good thing that in recent years cardio-oncology developed. So initially the patient that were going for cancer treatment, they were not monitored very closely. So they only end up in cardiology clinic when they are having some cardiac events already. So thanks to the lot of development and growth in the cardio-oncology field, now most patients who going for a long-term cancer treatment, they are closely monitored by cardiology clinics.   Cindy St. Hilaire:        Got it. So they can often catch it before a symptom or an event. That's wonderful.   Hind Lal:                     Yeah, so there's a lot of development in monitoring.   Cindy St. Hilaire:        Wonderful. So you were really interested in figuring out why ponatinib induces cardiotoxicity and you mentioned that really up until now it's been very difficult to study and that's because of the limitation of available murine models. If you just inject a wild type mouse with ponatinib, nothing happens really. So what was your approach to finding relatively good murine models? How did you go about that?   Hind Lal:                     So this is the top scientific question you can ask. So like science, the field is try and try again. So initially this is the first paper with the ponatinib toxicity using the real in vivo models. Any paper before this including ours studies published, they were done on the cellular model in hiPSC, that isolated cardiomyocytes. So you directly putting the ponatinib directly the isolated cells. So this is first case when we were trying to do in vivo, maybe other attempt in vivo but at least not published. So first we also treated the animals with ponatinib and that failed, we don't see any cardiotoxic effect. And then when we going back to the literature, the clinical data is very, very clear from pharmacovigilance that ponatinib is cardiotoxic in humans. So when we're not able to see any phenotype in mouse, we realize that we are not mimicking what's happening in the humans.   So we certainly missing something. Now once again I quote this COVID-19, so many people get infected with COVID-19 but people are having preexisting conditions are on high risk to developing CVD. So there was some literature on that line. So we use this very, very same concept that if there is preexisting conditions, so likely who'd have developing future cardiac event will be more. So we use two model in this paper one atherosclerosis model which is APoE null mice mice, another is tag branding which is pressure overload model for the heart and as soon as we start using what we call comorbidity model like patient is having some preexisting conditions and we very clearly see the robust defect of ponatinib on cardiac dysfunction.   Cindy St. Hilaire:        Yeah, it's really, really well done and I really like that you use kind of two different models of this. Do you think it's also going to be operative in maybe like the diabetic mirroring models? Do you think if we expand to other comorbidities, you might also recapitulate the cardiotoxicity?   Hind Lal:                     So you got all the best questions.   Cindy St. Hilaire:        Thank you. I try.   Hind Lal:                     So because this is CML drug and lot of the risk factor for cardiovascular and cancer are common and even metabolic disease. So most of the time these patients are elderly patients and they're having metabolic conditions and most of the time they have blood pressure or something CVD risk factors. So I agree with you, it'll be very relevant to expand this to the diabetes or metabolic models, but these were the first study, we put all our focus to get this one out so news is there then we can expand the field adding additional models et cetera. But I agree with you that will be very logical next step to do.   Cindy St. Hilaire:        Yeah. And so I guess going back to what you know from the human study or the clinical trials or the human observations, are different populations of patients with CML more predisposed to cardio toxicity than others or is that not known yet?   Hind Lal:                     So one other area called pharmacovigilance. So what pharmacovigilance does patient all over the world taking these drugs. So WHO have their own vigilance system and FDA have their own, so it's called BG-Base for the WHO and it's called the FAERS for the FDA. So one can go back in those data sets and see if X patient taking this Y drug and what kind of symptoms or adverse effect they are seeing and if these symptoms are associated with something else. So there is data that if patients having CVD risk factor, they are more prone to develop ponatinib induced cardiac events. But it needs more polish like you asked the just previous question, diabetes versus maybe blood pressure means hypertension, atherosclerosis, or thrombosis. So it has not been delineated further but in a one big bucket if patients are having CVD risk factor before they are more prone and more likely to develop the cardiac events.   Cindy St. Hilaire:        So after you established that these two murine models could pretty robustly recapitulate the human phenotype, what did you do next? How did you come upon the S100A8/A9-NLRP3-IL-1β signaling circuit? How did you get to that?   Hind Lal:                     So in basic science work, whenever we do mouse is called until we get there is cardiac dysfunction, it's called phenotype, right? So mouse had a cardiac phenotype. So next step is, "Why? What is leading to that phenotype?" That's what we call mechanism. So there the best idea to fit the mechanism is using one of the unbiased approaches like you do unbiased proteomics, unbiased RNC analysis, something like this that will analyze the entire transcript like RNC and say, "Okay, these pathway are," then you can do further analysis that will indicate these pathway are different, are altered. So in this case we used RNC analysis and it came out that this yes A8 and yes A9, 100A8 and nine, they were the most upregulated in this whole set. And thereafter we were very lucky. So we started this study at Vanderbilt, where my lab was and thereafter we very lucky to move here and found Sultan who had a lot of experience with this inflammation and immune system and then Sultan may add something on this so he'll be the better person to say something on this.   Tousif Sultan:              So after our RNC analysis, so we got this S100A8 and nine as top hit with the ponatinib treatment. So then we validated this finding with our flow cytometric, qRT PCR aand then we started which pathway is going to release cytokine and all that. So we found that is NLRP3 inflammasome.   Cindy St. Hilaire:        Yeah and well and I guess maybe step back, what is S100A8/A9? What are those? Tousif Sultan:              Yeah, S10A8/A9 is a calcium binding protein. So that's also called alarmin and they basically binds with the pathogen associated pattern and other TLR2 like receptors and then start inflammatory pathway to release cytokine and all that and it's stable in heterodimer form. So S100A8 heterodimer with A9 and then bind with TLR and a start in this inflammatory pathway.   Cindy St. Hilaire:        And what type of cell is that happening in? Is that happening in the immune cells only or is it also in the cardiomyocyte, or...?   Tousif Sultan:              Yeah, we have included all this data. So from where this alarmin is coming with ponatinib treatment, so literature also suggested that neutrophils and monocytes, those cells are the potential to release the alarmin. So here we also found these two type of cells, neutrophils and monocytes. They release huge alarmin with the treatment of ponatinib.   Cindy St. Hilaire:        And so really taking this really neat mechanism to the next level, you then tried attenuating it by using broad anti-inflammatory steroid dexamethasone but also by targeting these specific components, the NLRP and the S100A specific inhibitors and they worked well. It worked really nicely. Does your data show that any of these therapies work better than the other and then are these viable options to use in humans?   Hind Lal:                     Yeah, we have some data in the paper. Are very broad which help a lot in COVID patients, far very acute infections. So in this case, situation is very different cause most of CML patients will going to take ponatinib for lifelong, there is no remission, right? So in those case, its certainly not a very attractive option. We have shown data in the paper that dexamethasone help with the heart but lead to some metabolic changes. So we have compared those with the NLRP3 inhibitors, those metabolic alterations, dexa versus the NLRP3 inhibitors, CY-09. And we demonstrated that targeting is specifically with paquinimod, our NLRP3 inhibitor CY-09, feel better. It can still rescue the cardiac phenotype without having those adverse effect on metabolic parameters.   Cindy St. Hilaire:        That's wonderful. Do you think though that because you have to take ponatinib for life, that long-term NLRP inhibition would also cause problems or...?   Hind Lal:                     So because not every patient who taking ponatinib would develop the cardiac phenotype, right? Which is like a 10%, 12%, patient developing cardiac dysfunction. So I think someone like I strongly believe paquinimod, which is inhibitor of S100A9, will be really good option or at least we have enough data that make us nail for at least a small clinical trial. And we quickly moving on that. At UAB we have our clinical cardio-oncology program and we are already in touch with the director for the clinical cardio-oncology program. So what we trying to do in that small trial is if one of the standard therapy for heart like beta blocker or ARBs inhibitor, is there any preference like one work better than the other in the standard care? So first we doing that project, then we obviously looking forward if one small clinical trial can be done with paquinimod. I strongly believe it should be helpful.   Cindy St. Hilaire:        That is wonderful. And so do you think... There's other chemotherapeutic agents or probably even other non-cancer drugs that cause cardiotoxicity, do you think this mechanism, this pathway, this S100A-NLRP-IL-1β axis is operative in all cardiotoxicities or do you think it's going to be very specific to the ponatinib?   Hind Lal:                     So it's certainly not all, but it'll be certainly more than ponatinib. So in our lab we are using another kinase inhibitor, which is osimertinib and it's not published yet, but now we know that it's also cardiotoxic because it's taking metabolic root or energetics disruption but not this pro-inflammatory part, but we're doing another project which is strep pneumonia induced cardiac dysfunction, which is called pneumonia. So strep pneumoniae, which leads to the pneumonia ,and lot patient die because of the failing heart we see here in the hospitals and we see these pathways operational over there and we gearing up to do clinical trial on that aspect as well, but it's not generalized like all kind of heart will have the same mechanism.   Cindy St. Hilaire:        It's wonderful to see you're already taking those next steps towards really kind of bringing this to a translational/clinical study. So what was the most challenging aspect of this study?   Tousif Sultan:              The challenging aspect, ponatinib is a kinase inhibitor and that was surprising for us how it's activating immune cells. Generally kinase inhibitors, inhibits all the cells like that. So that was challenging. So we repeated it many times did in vitro experiment to confirm that. So we just added, just treated in vitro immune cells with the ponatinib and confirmed it. So that was little challenging.   Cindy St. Hilaire:        So what's next? You mentioned you're going to try some clinical trials, early stage clinical trials. What's next mechanistically, what do you want to go after?   Hind Lal:                     So what we are doing next and we are very, very eagerly trying to do that. So what it was done, we used the cardiac comorbidity models, but as you know, anybody who will take ponatinib will have cancer, right? So we strongly believe that we miss one factor. There was no cancer on these. So that is very logical next step. What that will allow us to do, what rescue experiment we'll have done in this paper. So we saw, "Okay, this rescue the cardiac phenotype, which is taken care of now," but very same time, we not able to demonstrate that this is happening without hurting the cancer efficacy. So if we have the dual comorbid mouse, which have CML a real thing and we have cardiac thing, then that will allow us to demonstrate, "Okay, we got something that can take care of the cardiac problem without hurting the efficacy on the cancer." And it will be best if you also help little bit to more potentiate the cancer efficacy.   Cindy St. Hilaire:        Yes. Excellent. Well, congratulations on a beautiful study, really exciting findings. Dr Lal and Dr Sultan, thank you so much for taking the time to talk with me today.   Tousif Sultan:              Thank you so much.   Hind Lal:                     Well thank you, Cynthia. We really appreciate your time. Thank you for having us.   Cindy St. Hilaire:        Yeah, it was great.   Cindy St. Hilaire:        That's it for our highlights from the February 3rd and February 17th issues of Circulation Research. Thank you so much for listening. Please check out the Circulation Research Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, Dr Hind Lal and Dr Tousif Sultan. This podcast is produced by Ishara Ratnayake, edited by Melissa Stoner and supported by the editorial team at Circulation Research. Some of the copy text for the highlighted articles was provided by Ruth Williams. I'm your host, Dr Cynthia St. Hilaire, and this is Discover CircRes, you're on-the-go source for most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association 2023. And the opinions expressed by the speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, please visit ahajournals.org.  

This month on JHLT: The Podcast, the JHLT Digital Media Editors review two studies from the February issue of The Journal of Heart and Lung Transplantation—and bring in a couple of experts to help them make sense of some new technology.   First, the editors explore a pre-clinical study entitled “The dynamic cellular landscape of grafts with acute rejection after heart transplantation,” which comes from Kong and colleagues at Zhejiang University in Hangzhou, China.   Single cell technologies are emerging as non-biased techniques to discover novel biological pathways in a variety of pre-clinical models and in human tissue both in health and disease. To help the editors—and you!—understand single cell approaches and this study, JHLT editors Ben Kopecky, MD, PhD and Kory Lavine, MD, PhD, from the Washington University St. Louis, appear in the episode to explore the methodology and what the study tells us.   Second, the editors welcome author Sam Rayner, MD from the University of Washington in Seattle, USA, to discuss the paper by Hirsch and colleagues, “Circulating markers of inflammation and angiogenesis and clinical outcomes across subtypes of pulmonary arterial hypertension.”   When considering differences in pathophysiology of the subtypes of PAH, changes in biomarkers in angiogenesis and inflammation may provide useful insights and potential therapeutic targets. The authors of this study prospectively looked at 33 biomarkers of angiogenesis and inflammation in a cohort of patients across various PAH etiologies, and made correlations to clinical outcomes.   Follow along at www.jhltonline.org/current, or, if you're an ISHLT member, log in at ishlt.org/journal-of-heart-lung-transplantation.  Don't already get the Journal and want to read along? Join the International Society of Heart and Lung Transplantation at www.ishlt.org for a free subscription, or subscribe today at www.jhltonline.org.    

In this episode of the JIM Podcast, Editor-in-Chief Richard McCallum speaks with Dr. Himanshu Deshwal on advances in the management of pulmonary arterial hypertension. Dr. Deshwal is a fellow in Pulmonary Disease and Critical Care Medicine at the NYU Grossman School of Medicine. He received his M.B.B.S from the Armed Forces Medical College (AFMC)in Pune, India and completed his internal medicine residency with the Cleveland Clinic Foundation Program.

Dr. Harrison Farber, a pulmonologist and director of the Pulmonary Embolism Response Team at Tufts Medical Center discusses a chronic rare disease that affects the circulatory system in the lungs and directly affects the ability of the lungs to function.Pulmonary Arterial Hypertension, or PAH, is characterized by shortness of breath, dizziness, and chest pressure. Dr. Harrison Farber joins us to discuss the impact of COVID-19 on PAH patient care.

Moderator Nicholas A. Kolaitis, MD, MAS, and journal CHEST® authors Daniel Lachant, DO, and R. James White, MD, PhD, discuss the article, "Cardiac Effort to Compare Clinic and Remote 6-Minute Walk Testing in Pulmonary Arterial Hypertension," which was published in the December issue. DOI: https://doi.org/10.1016/j.chest.2022.06.025

Beth Slaunwhite lives with a rare, progressive disease called Pulmonary Arterial Hypertension, but the road to an accurate diagnosis wasn't easy. PAH causes shortness of breath, fainting... symptoms you might see with more common conditions like asthma, which is why PAH often goes misdiagnosed.

Impact: Pulmonary Artery Denervation for PAH

This month on Episode 41 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the September 30 and October 14 issues of Circulation Research. This episode also features an interview with Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis, to discuss their study, Transcriptional and Immune Landscape of Cardiac Sarcoidosis.   Article highlights:   Tian, et al. EV-Mediated Heart Brain Communication in CHF   Wleklinski, et al.  Impaired Dynamic SR Ca Buffering Causes AD-CPVT2   Masson, et al. Orai1 Inhibition as a Treatment for PAH   Li, et al. F. Prausnitzii Ameliorates Chronic Kidney Disease   Cindy St. Hilaire:        Hi, and welcome to Discover Circ Res, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cynthia St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to highlight articles from our September 30th and October 14th issues of Circulation Research.                                           I'm also going to have a chat with Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis, and we're going to discuss their study Transcriptional and Immune Landscape of Cardiac Sarcoidosis. But before I get to the interview, I'm going to highlight a few articles.   Cindy St. Hilaire: The first article I'm going to share is Extracellular Vesicles Regulate Sympathoexcitation by Nrf2 in Heart Failure. The first author of this study is Changhai Tian, and the corresponding author is Irving Zucker, and they are at University of Nebraska. After a myocardial infarction, increased oxidative stress in the heart can contribute to adverse cardiac remodeling, and ultimately, heart failure. Nrf2 is a master activator of antioxidant genes, suggesting a protective role, but studies in rats have shown its expression to be suppressed after MI, likely due to upregulation of Nrf2-targeting microRNAs. These microRNAs can also be packaged into vesicles and released from stressed heart cells.   Now, this group has shown that rats and humans with chronic heart failure have an abundance of these microRNA-containing EVs in their blood. In the rats with chronic heart failure, these extracellular vesicles were found to be taken up by neurons of the rostral ventrolateral medulla, RVLM, wherein the microRNA suppressed Nrf2 expression. The RVLM is a brain region that controls the sympathetic nervous system, and in the presence of EVs, it is ramped up by sympathetic excitation. Because such elevated sympathetic activity can induce the fight or flight response, including increased heart rate and blood pressure, this would likely worsen heart failure progression. The team, however, found that inhibiting microRNAs in the extracellular vesicles prevented Nrf2 suppression in the RVLM and sympathetic activation, suggesting the pathway could be targeted therapeutically.   Cindy St. Hilaire:        The next article I want to highlight is titled, Impaired Dynamic Sarcoplasmic Reticulum Calcium Buffering in Autosomal Dominant CPVT2. The first author of this study is Matthew Wleklinski, and the corresponding author is Bjӧrn Knollmann, and they are at Vanderbilt University.   Exercise or emotional stress can prompt the release of catecholamine hormones, which induce a fast heart rate, increased blood pressure, and other features of the fight or flight response. For people with catecholaminergic polymorphic ventricular tachycardia, or CPVT, physical activity or stress can cause potentially lethal arrhythmias. Mutations of calsequestrin-2, or CASQ2, which is a sarcoplasmic reticulum calcium-binding protein, is a major cause of CPVT, and can be recessive or dominant in nature.   For many recessive mutations, disease occurs due to loss of CASQ2 protein. This group investigated a dominant lysine to arginine mutation in this protein, and found by contrast, protein levels remain normal. In mice carrying the mutation, not only was the level of CASQ2 comparable to that in control animals, but so, too, was the protein's subcellular localization. The mutation instead interfered with CASQ2's calcium binding or buffering capability within the sarcoplasmic reticulum. The result was that upon catecholamine injection or exercise, the unbound calcium released prematurely from the sarcoplasmic reticulum, triggering spontaneous cell contractions. In uncovering this novel molecular etiology of CPVT, the work provides a basis for studying the consequences of other dominant CASQ2 mutations.   Cindy St. Hilaire:        The next article I want to highlight is from our October 14th issue of Circulation Research, and the title of the article is ORAI1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension. The first author is Bastien Masson, and the corresponding author is Fabrice Antigny, and they're from Inserm in France. In pulmonary arterial hypertension, the arteries of the lungs become progressively obstructed, making it harder for the heart to pump blood through them, ultimately leading to right ventricular hypertrophy and heart failure. A contributing factor in the molecular pathology of pulmonary arterial hypertension is abnormal calcium handling within the pulmonary artery smooth muscle cells. Indeed, excess calcium signaling causes these cells to proliferate, migrate, and become resistant to apoptotic death, thus leading to narrowing of the vessel.   This group now identified the calcium channel ORAI1 as a major culprit behind this excess signaling. Samples of lung tissue from pulmonary arterial hypertension patients and a pulmonary arterial hypertension rat model had significantly upregulated expression of this channel compared with controls. And in patient pulmonary arterial smooth muscle cells, the high ORAI1 levels resulted in heightened calcium influx, heightened proliferation, heightened migration and reduced apoptosis. Inhibition of ORAI1 reversed these effects. Furthermore, in pulmonary hypertension model rats, ORAI1 inhibition reduced right ventricle systolic pressure and attenuated right ventricle hypertrophy when compared with untreated controls. This study indicates that ORAI1 inhibitors could be a new potential target for treating this incurable condition.   Cindy St. Hilaire:        The last article I want to share is titled Faecalibacterium Prausnitzii Attenuates CKD via Butyrate-Renal GPR43 Axis. The first author of this study is Hong-Bao Li, and the corresponding author is Tao Yang, and they are from the University of Toledo.   Progressive renal inflammation and fibrosis accompanied by hypertension are hallmarks of chronic kidney disease, which is an incurable condition affecting a significant chunk of the world's population. Studies indicate that chronic kidney disease is linked to gut dysbiosis. Specifically, depletion of lactobacillus bifidobacterium and faecalibacterium, prompting investigations into the use of probiotics. While supplements including lactobacillus and bifidobacterium have shown little effectiveness in chronic kidney disease, supplementations with F. prausnitzii have not been investigated.   Now, this group has shown in a mouse model of chronic kidney disease that oral administration of F. prausnitzii has beneficial effects on renal function, reducing renal fibrosis and inflammation. This bacterial supplementation also produced the short chain fatty acid butyrate, which was found to be at unusually low levels in the blood samples from the CKD model mice and from chronic kidney disease patients. Oral supplementation with this bacterium boosted butyrate levels in the mice, and in fact, oral administration of butyrate itself mimicked the effects of the bacteria. These findings suggest that supplementation with F. prausnitzii or, indeed, butyrate could be worth investigating as a treatment for chronic kidney disease.   Cindy St. Hilaire:        Today I have with me Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis, and we're going to talk about their paper, Transcriptional and Immune Landscape of Cardiac Sarcoidosis. This is in our September 30th issue of Circulation Research. Welcome, and thank you for taking the time to speak with me today.   Chieh-Yu Lin:             Thank you for inviting us. It's a great honor to be here today.   Kory Lavine:               Thank you.   Cindy St. Hilaire:        Really great paper, ton of data, and hopefully, we can pick some of it apart. But before we get into it, I actually want to just talk about sarcoidosis generally. I know it's a systemic inflammatory disease that has this kind of aggregation of immune cells as its culprit, and it can happen in a bunch of different organs. It's mostly in the lung, but it's also, like you're studying, in the heart. Can you just give us a little bit of background? What is sarcoidosis, and how common is cardiac sarcoidosis?   Chieh-Yu Lin:             Well, this is actually a great question, and I'll try to answer it. You actually capture one of the most important kind of features for sarcoidosis. It happens in all kind of organ system, mostly commonly in lung, in lymph nodes, but also in heart, spleen, even in brain, or even orbit, like eyes. It's really a truly multisystemic disease that has been characterized by this aggregate of macrophages, or myeloid cells, with scattered multinucleated giant cells, as the name implies, have multiple nuclear big, chunky, cells that form an aggregate. That's kind of like a pathognomonic feature for sarcoidosis, whether it's happening in lung, in the heart. When any organ system, a lot of studies has been done, but as of now, a very clear pathogenesis or mechanism has been, I would say, still pretty elusive, or still remain quite unclear, despite all the great effort has been made in this field. The other thing is that a lot of the studies actually focusing on pulmonary sarcoidosis for good reasons. Actually, that's one of the most common manifestations. For cardiac sarcoidosis, although it's only effect in probably, I would say depends on the data, 20% to 30% of the outpatient that with sarcoidosis, with or without lung involvement. It's actually carry a very significant clinical implications as of matter that the presentation of cardiac sarcoidosis can be devastating and sometimes actually fatal. Some of the study actually show that cardiac sarcoidosis actually higher, up to 80%, just because the first presentation's actually, unfortunately, sudden cardiac death. That's why Kory and I, we teamed up. I'm a cardiothoracic pathologist, so in my clinical practice I see specimens and samples from human body, from patient suffer from sarcoidosis, both in lung, lymph node, and heart. Kory is an outstanding heart failure, heart transplant cardiologist, see the other end, which is the patient care. This disease, specifically in heart, its presentation and its pathogens in heart, really attracts our attention.   Cindy St. Hilaire:        Do we know any or some of the potential causes? Why it would start, maybe in a different patient population, but also in the heart versus the lung? Do we know anything about that process?   Kory Lavine:              We know nothing about it. Sarcoid has no known etiology. There's been thoughts in the past that it may be driven by infection, the typical pathogens or autoimmune ideologies, but really, there's little data out there to support those possibilities. Right now, the field's wide open. The other challenge is we don't really have a good way to treat this disease, so a lot of the therapies available are things like steroids, which can have some effect on the disease but carry a lot of risk of complications. The other agents that we sometimes use to lower the doses of steroids, things like methotrexate and azathioprine, are only modestly effective.   These are really the motivation for Chieh-Yu and myself to pursue this. We don't really know what causes the disease, and we don't really have very good treatments. We really wanted to take the first step, that's to study the real disease, and understand what are the pathologic cell types that are present within the granuloma, which is these aggregation of immune cells that Chieh-Yu was speaking about.   Cindy St. Hilaire:        What is actually happening at the beginning of this disease? These granulomas form, and then what is the pathological progression in the heart? What goes on there?   Chieh-Yu Lin:             This is actually another great question that I will say there's not much that has been discovered because, especially in human tissue, every time we have a sample, it's actually a kind of time point. We cannot do a longitudinal study. But in general speaking, very little is known about how it's initiated because it will need to accumulate to a certain disease burden for this to have a clinical symptom sign and be manifested, and then being clinically studied. We do know that in both heart and lung after treatment of progressions, it's usually in, a general speaking, going through a phase from a more proliferative means that it's creating more granulomas, more  inflammatory cell aggregate, to a more fibrotic phase. Means that sometimes you actually see the granuloma start to disappear or dissipate, and then showing this kind of dense collagen and fibrosis. That has been commonly documented in both lung and heart sarcoidosis. The other things is that very difficult to study this disease that we do not have a great animal model, so we cannot use animal model to try to approximate or really study the disease pathogenesis. There are several animal models they try to use microbacteria or infectious agents, and these infectious agents can create morphologically similar granuloma, per se, but just like in human body. For instance, patients suffer from TB in their lung, biopsy will show this. But clinically, these are two very distinct disease entities, even though they look alike. Even in the heart, one of the conditions that we study in our paper is giant cell myocarditis, as the name implying having multinucleated giant cells granuloma. It looks really alike under microscopy for pathologists like me, but their clinical course in response to treatment is drastically different. This type of barriers and in the current limitations of our study tool makes, as Kory just said, this is really a wide open. We just know so little despite all the effort.   Cindy St. Hilaire:        Yeah. I'm guessing based on this granuloma information, to start with, the obvious question you went after is going after the immune cell populations that possibly contribute to sarcoidosis. To do this, because you have the human tissue, you went for single cell transcriptional profiling, which is a great use of the technology. But what biological sources did you use, and how did you go about choosing patient? Because the great thing about single cell is you can do just that, you can look at however many thousands of cells in one patient. But how do you make sure or check that that is broadly seen versus just a co-founding observation in that patient?   Kory Lavine:               We use explanted hearts and heart tissue from patients that underwent either heart transplantation or implementation of LVADs. It's a pretty big hunk of myocardium, and we're lucky to work with outstanding pathologists both at WashU, JU, as well as our collaborators at Duke. Between the two institutions, we're able to pull together a collection of tissues where we knew there were granulomas within that piece of tissue we analyzed. You bring up an important challenge. You need to make sure the disease and cause of the disease is present in the tissue that you're analyzing, otherwise you'll not come up with the data that really is informative.   Chieh-Yu Lin:             Kory beautifully answered the question, but I just wanted to add one little thing, and that's also why we use various different modalities. Some of them is more inside you, like the NanoString Technologies' spatial transcriptomic. You can visualize and confirm that we are studying the phenomenon that has been described for sarcoidosis, and then using multichannel immunofluorescence to validate our sequencing data, to complement such limitations of certain technology.   Cindy St. Hilaire:        Especially, I feel like with this diseased tissue that it's such a large tissue, there's so much information, it's really hard to dig in and figure out where the signal is. This was a wonderful paper for kind of highlighting, integrating all these new technologies with also just classical staining. Makes for great pictures as well. How does this cellular landscape of cardiac sarcoidosis compare to a normal heart? What'd you find?   Chieh-Yu Lin:             This is a great question. Compared to normal heart, we have been talking about this accumulation of macrophages with scattered multinucleated giant cells. For the similar landscape, first and foremost, you do not see those type of accumulations in brain microscopy or by myeloid markers in the heart. Although, indeed, in even normal heart tissue we have rest and macrophages. It just doesn't form such morphological alterations. But then we dive deep into it, and then we found that from a different cell type perspective, we realized that the granuloma is composed by several different type of inflammatory cells, with most of the T cells and NKT cells kind of adding periphery. The myeloid cells, including the multinucleated giant cells also, are kind of in the center of the granuloma of the sarcoidosis. Then, we further dive in and realize that there are at least six different subtype of myeloid cells that is contributing to the formation of this very eye-catching distinctive granular malformations, and to just never feel first off and foremost, of course, is those multinucleated giant cells that is really distinct, even on the line microscopy] routine change stand.   And then we have a typical monocyte that's more like a precursor being recently recruited to the heart, and we finally sent the other four different type of myeloid cell that carry different markers, and then improving the resident macrophages. Especially for me as a pathologist, I'm using my eye and looking at stand every day, is actually these six type of cells, myeloid cells, actually form a very beautiful special kind of distribution with the connections or special arrangement with all different type, kind of like multinucleated giant cell in the middle, flanked by HLA-DR positive epithelioid macrophages, kind of scatter, and then with dendritic cells and a typical monocyte at the peripheral, and then resident macrophage kind of like in the mix of the seas of granuloma information. All these are distinct from normal heart tissues that does carry a certain amount of macrophages, but just don't form this orchestrated architectural distinct structure that's composed of this very complicated landscape.   Cindy St. Hilaire:        Those images, I think it was figure six, it's just gorgeous to look at, the model you made. One of the questions I was thinking is there must be a significance between these cells that are on the periphery and those that are in the center of this granuloma. Do you have an idea or can we speculate as to are some more cause and some more consequence of the granuloma? Were you able to capture any more information about maybe the initiating steps of these from your study?   Kory Lavine:              That's a great question, and a question the field has had for a long time. Now, we know there's different populations of cells. The single cell data allows us to understand what are the transcriptional differences and distinctions between them to gain some insights. One thing that we do know from the field is that disease activity correlates with mTOR activity within these granulomas. We took advantage of phospho-S6 kinase staining as a downstream marker of mTOR activity, and Ki-67 is a marker of self proliferation.   Which of these populations within the granuloma might be most active with respect to mTOR and respect to proliferation? If you ask most people in the field, they would jump up and say, "It's the giant cell in the middle." We found that that's not actually the case at all. It's the macrophages that surround the giant cell, the ones that are HLA-DR positive, the epithelioid macrophages, and the ones that are SYLT-3 positive that are scattered around them. That's really interesting and could make a lot of sense, and leads to hypothesis that perhaps activation mTOR signaling within certain parts of the granuloma might be sufficient to set up the rest of the architecture. That's something that we can explore in animal models, and are doing so to try to create a cause and effect relationship. Cindy St. Hilaire:        Yeah, and I was actually thinking about this, too, in relation to kind of the resident macrophages versus infiltrating macrophages or even just infiltrating immune cells. Do you know the original source of the cells that make up the granuloma? Is it mostly resident immune, or are they recruited in?   Kory Lavine:               We can make predictions from the single cell data where you can use trajectory analysis to make strong predictions about what the origin of different populations might be. What those analyses predicted is that the giant cells and the cells that surround the giant cells, the HLA-DR positive and SYLT-3 positive macrophages, come from monocytes. That's the prediction, and, of course, resident macrophages do not. However, that prediction has to be tested, and that's the beauty and importance of developing animal models. The wonderful thing today is we now have genetic tools to do that. We can ask that question.   Cindy St. Hilaire:        I don't know. Maybe you don't want to spoil the lead of the next paper, but what kind of mouse model are you thinking about trying?   Kory Lavine:               Yeah. First of all, let me talk about the tools that are available, because they're published in Circulation Research, of course. We have a nice tool to specifically mark, track and delete in tissue resident macrophages using a CX3CR1 ERT pre-mouse, and taking advantage of the concept that tissue macrophages don't turn over from monocytes and turn over from themselves. We can give tamoxifen to label all monocytes macrophages in Dcs with that CRE, and then wait a period of time where only the resident macrophages remain labeled. We can use that trick to modulate mTOR signaling as a first step, and ask whether mTOR signaling is required in that population. We've now developed a new genetic tool to do the same thing in just recruited macrophages.   Cindy St. Hilaire:        What was the most challenging aspect of this study? There's a lot of moving parts. I'm sure probably the data analysis alone is challenging, but what would you say is the most challenging?   Kory Lavine:               I think you alluded to this early on, but the most challenging thing is collecting the right tissues to analyze, and that's not a small feat or a small effort here. All the technologies are a lot of fun, and everything works so well today compared to many years ago when we trained, so it's an exciting time to do science. The most challenging and time-consuming component was assembling a group of tissues that we could do single-cell sequencing on between our group and our colleagues at Duke, and then creating validation cohorts that we did across several different institutions, including our own as well as Stanford. That team effort in building that team is the most important, challenging, and honestly, enjoyable part of this.   Chieh-Yu Lin:             I cannot agree more what Kory just said. I think that that's the challenging and the fun part, and that we're very fortunate to really have a great team to tackle this questions in multiple from multiple institute. I just want to add one more thing that, particularly for me as a cardiopathologist, one of the hardest things is I've known how to look or diagnose sarcoidosis for years, but seeing the data emerging that is so complicated and then beyond my reliable eyes in understanding, it's kind of mentally very challenging but very fun to really open and broaden the vision. It's not just how it looks like just giant cells in macrophages.   Cindy St. Hilaire:        What do you think about in terms of diagnostics or even potential therapies? How do you think this data that you have now can be leveraged towards those objectives, whether it's screening for new cell types that are really key to this granuloma formation versus therapeutically targeting them?   Kory Lavine:              This study opens new doors, and right now, diagnosis of sarcoids islimited by trying to biopsy, which, in the heart, is limited by sample bias. You certainly can biopsy the wrong area because you don't know whether a granuloma is in the area or not. We do do some cardiac and other imaging studies like FDG-PET scans, which are helpful but are not perfect, and each of them has their individual limitations. One of the beauties of our study is it identifies new markers of macrophage populations that live within the granuloma, many of which are unique to this disease.   That suggests that there's maybe an opportunity to develop imaging tracers that can identify those populations more specifically than our current PET imaging studies do, which rely simply on glucose uptake. It also opens up the possibility that we may able to take blood samples and identify some of these cell types within the blood, and have more simple testing for our patients. I think in terms of therapy, you alluded to it earlier, these concepts about mTOR signaling, that could be a new therapeutic avenue that needs to be rigorously explored in preclinical models. We're lucky already to have very good mTOR inhibitors available in clinical practice today.   Cindy St. Hilaire:        Obviously, opening new doors is amazing because it's more information, but often a good study leads to even more questions to be asked. What question, or maybe what questions, are you guys going to go after next?   Chieh-Yu Lin:             Well, that list is very long, and then that's actually the exciting thing about doing this research. There's no bad questions, in some sense. All the way from diagnosis, management, monitoring, therapeutic, how we predict where the patient can respond, that's the whole clinical side. Even the basic science side, we still haven't really answered the question, although our data suggests where that multinucleated giant cells coming from. It's very eye catching. How do they form, even though our data suggests it's from the recruited macrophages. But that's still a long way from the recruited macrophage,  monocyte to that gigantic bag of nuclei in the very fluffy cytoplasm.   And then, how the granuloma, as we discussed earlier in this discussion, really initially from a relatively normal background myocardium to form this disease process. There are just so many questions that we can ask. There are, of course, several fronts that we would like to focus on. Kory already nicely listed some of them. First and foremost is actually to establish animal model to enable us to do more details in mechanistic studies, because human tissue, as good as it is, it's kind of like a snapshot, just one time point, and it really limits our ability to test our hypothesis. Animal model, certainly, is one of the major directions that we are going forward, but also the other side, like more clinical science also to develop novel noninvasive methodologies to diagnose and to hopefully monitor this patient population in a better way.       Cindy St. Hilaire:        Well, it's beautiful work. I was actually reading this paper this weekend at a brunch place just next door to my house, and the guy sitting next to me happened to see over my shoulder the title and said that his father had passed away from it. This is hopefully going to help lots of people in the future, and really help to make the models that we need to ask, "What's happening in this disease?" Thank you so much for taking the time to speak with me, and congratulations on what seems to be a landmark study in understanding what's going on in this disease.   Chieh-Yu Lin:             Thank you so much. It's a pleasure.   Cindy St. Hilaire:        That's it for our highlights from the September 30th and October 14th issues of Circulation Research. Thank you so much for listening. Please check out the Circ Res Facebook page, and follow us on Twitter and Instagram with the handle @CircRes, and hashtag Discover Circ Res. Thank you so much to our guests, Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis. This podcast is produced by Ashara Retniyaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy texts for highlighted articles was provided by Ruth Williams. I'm your host, Dr Cynthia St. Hilaire, and this is Discover Circ Res, your on-the-go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors of the American Heart Association. For more information, please visit ahajournals.org.  

GuestHilary M. DuBrock, MDMayo Clinic RochesterHostsJennifer D. Duke, MD Mayo ClinicP.J. Gary, MD Mayo ClinicShow NotesIf you enjoyed this content, please follow or subscribe and leave us a review! Access the ATS Reading List.Recommended Reading Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809-818.  Supplement to: Pulido T et al. 2013.  Galiè N, Barberà JA, Frost AE, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015;373(9):834-844. doi:10.1056/NEJMoa1413687 Supplement to: Galiè et al. 2015.  Simonneau G, Channick RN, Delcroix M, et al. Incident and prevalent cohorts with pulmonary arterial hypertension: insight from SERAPHIN. Eur Respir J. 2015;46(6):1711-1720. doi:10.1183/13993003.00364-2015

On this episode, we discuss pulmonary arterial hypertension (PAH) and the pharmacotherapy options that are currently available.  Cole and I are happy to share that our listeners can claim ACPE-accredited continuing education for listening to this podcast episode! We have continued to partner with freeCE.com to provide listeners with the opportunity to claim 1-hour of continuing education credit for select episodes. To earn credit for this episode, visit the following link and select this episode from the list of accredited episodes: Link to PAH post-activity test For existing Unlimited freeCE members, this CE option is included in your membership benefits at no additional cost! Members can simply follow the link above to take the post-test and evaluation for this activity. Use the password CENTRAL (all caps) to unlock the post-test for this episode. But if you're not currently a freeCE member, we definitely suggest you explore all the benefits of their Unlimited Membership on their website and earn CE for listening to this podcast. CorConsult Rx listeners can save 15% off the purchase of an unlimited membership by entering the discount code “PODCAST2022” at checkout, or by clicking the following link in the description https://hubs.ly/Q012N0H60 Thanks for listening! We want to give a big thanks to our main sponsor Pyrls. Try out their drug information app today. Visit the website below for a free trial: www.pyrls.com/corconsultrx If you want to support the podcast, check out our Patreon account. Subscribers will have access to all previous and new pharmacotherapy lectures as well as downloadable PowerPoint slides for each lecture. You can find our account at the website below:  www.patreon.com/corconsultrx If you have any questions for Cole or me, reach out to us on any of the following: Text - 415-943-6116

Welcome back Rounds Table Listeners! We are back today with a variation on our Classic Rapid Fire Podcast! This week, Drs. Mike and John Fralick discuss two recent papers – one, exploring a novel method of vaccinating against RSV during pregnancy and the other, a review on the diagnosis and management of Pulmonary Arterial Hypertension. ...The post Episode 40 – RSV Immunization in Pregnancy and Pulmonary Arterial Hypertension appeared first on Healthy Debate.

Welcome back Rounds Table Listeners! We are back today with a variation on our Classic Rapid Fire Podcast! This week, Drs. Mike and John Fralick discuss two recent papers – one, exploring a novel method of vaccinating against RSV during pregnancy and the other, a review on the diagnosis and management of Pulmonary Arterial Hypertension. ... The post Episode 40 – RSV Immunization in Pregnancy and Pulmonary Arterial Hypertension appeared first on Healthy Debate.

Are you aware of the current trends regarding the diagnosis and treatment of pulmonary arterial hypertension? Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/972133?src=mkm_podcast_addon_972133

Pulmonary arterial hypertension is a rare condition that requires a thorough workup to evaluate for potential causes and right heart catheterization for definitive diagnosis and decision-making about treatment options. JAMA Associate Editor Kristin Walter, MD, MS, discusses the recent JAMA review article titled “Pulmonary Arterial Hypertension Classification, Diagnosis, and Treatment” with one of the authors, Nicole Ruopp, MD, assistant professor of medicine at Tufts Medical Center and Tufts University School of Medicine. Related Content: Diagnosis and Treatment of Pulmonary Arterial Hypertension