POPULARITY
7 episodes with heartmate
2 episodes with heartmate
2 episodes with heartmate
2 episodes with heartmate
3 episodes with heartmate
25. května 2025 je to deset let, co kardiochirurgové v IKEM poprvé miniinvazivně zavedli srdeční pumpu HeartMate 3. Do těla se nově dostala jen malým řezem v levém mezižebří namísto přístupu přes otevřený hrudník. Výkon má pro pacienty řadu výhod: rychlejší hojení, menší bolesti, a především méně komplikací. V IKEM Podcast výkon komentuje profesor Ivan Netuka, přednosta Kliniky kardiovaskulární chirurgie IKEM.
On this special episode of JHLT: The Podcast, the Digital Media Editors take a look back at the exciting science that was on display at ISHLT2025, the ISHLT 45th Annual Meeting & Scientific Sessions. Topics include: Telomere biology disorders and lung transplantation The meeting's special focus on cardiogenic shock The apixiVAD trial exploring low dose apixaban in HeartMate 3 LVADs Myocardial recovery on durable LVADs For the latest studies from JHLT, visit jhltonline.org/current, or, if you're an ISHLT member, access your Journal membership at ishlt.org/jhlt. Full-text abstracts of the meeting can also be found at the JHLT website. 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.
Returning for a second study this month, the JHLT Digital Media Editors invite first author Charlotte Van Edom to discuss the paper, “Apixaban plasma levels in patients with HeartMate 3 support.” As a cardiologist in training and a PhD candidate at the University Hospitals Leuven in Belgium, Van Edom's work focuses on hemocompatibility and mechanical circulatory support, covering both short-term and long-term support. The episode explores: The evolution of the use and understanding of direct oral anticoagulants (DOACs) during LVAD support, including the increased focus on Factor Xa inhibitors Encouraging findings from the study and what clinical practices might need to change if introducing apixaban Additional studies exploring DOACs in LVAD patients 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. Treat or research pulmonary vascular diseases? Check out the first April episode for a study on sotatercept in PAH patients. 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.
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.
JHLT: The Podcast returns with a year-end recap of 2024. Each Digital Media Editor shares one of their favorite studies from JHLT in 2024 for a quick recap of last year's excellent science in advanced heart and lung disease. Studies featured: · Cardiac magnetic resonance assessment of acute rejection and cardiac allograft vasculopathy in pediatric heart transplant Kikano, Sandra et al. JHLT May 2024 5(43):745-754 · A modular simulation framework for organ allocation Rose, Johnie et al. JHLT Aug 2024 8(43):1326-1335. · HeartMate 3 Snoopy: Noninvasive cardiovascular diagnosis of patients with fully magnetically levitated blood pumps during echocardiographic speed ramp tests and Valsalva maneuvers Schlöglhofer, Thomas et al. JHLT Feb 2024 2(43):251-260. · Factors associated with acute limb ischemia in cardiogenic shock and downstream clinical outcomes: Insights from the Cardiogenic Shock Working Group Kochar, Ajar et al. JHLT Nov 2024 11(43):1846-1856. 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. 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 AbbottTalks, Kartik Sundareswaran, PhD, divisional VP, global clinical and regulatory affairs, Abbott Heart Failure, discusses Abbott's pioneering work in heart failure care, focusing on technologies that improve outcomes and empower earlier interventions. Sundareswaran's path to MedTech began with a shift from computer engineering to biomedical research, where his early work studying blood flow patterns in children with congenital heart disease sparked a passion for solving cardiovascular challenges. This passion led him to roles at Thoratec, St. Jude Medical, and ultimately Abbott, where he has spent years advancing heart failure care. The conversation highlights Abbott's CardioMEMS™ Heart Failure System, a device enabling remote pulmonary artery pressure monitoring to reduce hospitalizations, and the HeartMate 3 LVAD, which provides life-extending support for patients with advanced heart failure. Sundareswaran also discusses the new TEAM-HF clinical trial, which combines CardioMEMS and HeartMate 3 to identify patients earlier and deliver timely, effective interventions. This conversation comes to you courtesy of our episode sponsor, Tecan Group Ltd. To learn more about how Tecan works with medical device companies, visit: https://partnering.tecan.com/ Thank you for listening to the AbbottTalks Podcast. Tune in and subscribe to DeviceTalks on all major podcast channels to never miss an episode.
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.
Welcome to the MassDevice Fast Five medtech news podcast, the show that keeps you up-to-date on the latest breakthroughs in medical technology. Here's what you need to know for today, March 13, 2024. Check out the show notes for links to the stories we discussed today at MassDevice.com/podcast. GE HealthCare and Mass General are bringing artificial intelligence to imaging. Fast Five hosts Sean Whooley and Danielle Kirsh discuss the partnership and how it can transform healthcare. Ascensia and Senseonics have announced new CGM cost savings. Hear more about some of the cost saving initiatives and the devices that are included in the initiatives. SS Innovations has used its surgical robot in mitral valve replacement procedures. Whooley talks about what the robot does and what people think about its performance. 3M CEO Mike Roman is stepping down as CEO and a successor has been named. Learn who is taking over the corner office and the optimism they bring to the role. A recent recall of Abbott's HeartMate communications system is Class I, according to the FDA. The Fast Five hosts talk about the reason behind the recall and if there have been any adverse reports.
CardioNerds (Dr. Josh Saef and Dr. Sumeet Vaikunth) join Dr. Sheng Fu, Dr. Payton Kendsersky, and Dr. Aniqa Shahrier from the Medical University of South Carolina for some off-shore fishing. They discuss the following featuring a patient with D-TGA and Eisenmenger's syndrome treated with a Heartmate 3. Expert commentary was provided by Dr. Brian Houston. The episode audio was edited by student Dr. Adriana Mares. A 39-year-old woman with a history of D-transposition of the great arteries (D-TGA) with prior atrial switch repair (Mustard) was admitted from the clinic with cardiogenic shock. She underwent right heart catheterization which demonstrated elevated biventricular filling pressures and low cardiac index. An intra-aortic balloon pump was placed, and the patient was evaluated for advanced therapies. A liver biopsy showed grade 3 fibrosis, which, in combination with her shock state, made her a high-risk candidate for isolated heart or combined heart-liver transplantation. After a multi-disciplinary discussion, the patient underwent a Heartmate III left ventricular assist device (LVAD) implant in her systemic right ventricle. Although she did well post-operatively, she was admitted after a month with recurrent cardiogenic shock, with imaging showing her inflow cannula had become perpendicular to the septum. The patient and family eventually decided to pursue comfort measures, and the patient passed. US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here. CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Case Media - D-TGA and Eisenmenger's syndrome treated with a Heartmate 3 Pearls - D-TGA and Eisenmenger's syndrome treated with a Heartmate 3 Early diagnosis of cyanotic congenital heart disease is paramount for treatment and prevention of future complications. Adult congenital heart disease requires a multi-disciplinary team for management in consultation with an adult congenital cardiology specialist. Eisenmenger syndrome is related to multiple systemic complications and has a high rate of mortality. Advancement in PAH medical management can offer noninvasive treatment options for some patients. Transthoracic echocardiography is the cornerstone for diagnosis. Other modalities (e.g. cardiac CT, cardiac MRI, invasive catheterization) can aid in diagnosis and management. Pearls - D-TGA and Eisenmenger's syndrome treated with a Heartmate 3 While advances in pediatric surgery have allowed many patients born with congenital heart disease to survive into adulthood, adult congenital heart disease (ACHD) patients are complex and prone to numerous adverse sequalae including arrhythmias, heart failure, valvular disease, and non-cardiac organ dysfunction. Heart failure can be a challenging presentation in ACHD patients due to a longstanding history of clinical compensation. Their unique and complex anatomy, as well as highly variable clinical presentation, present unique challenges when it comes to advanced heart failure options such as durable left ventricular assist devices (LVAD) or transplantation. While durable LVAD implantation is possible in patients with systemic right ventricles, anatomic compatibility is paramount and poses ongoing challenges in their management. Goals of care discussions should be had early, as options for treatment may be limited. Show Notes - D-TGA and Eisenmenger's syndrome treated with a Heartmate 3 What are some common sequelae in ACHD patients? ACHD patients are a heterogeneous population, but atrial tachycardias are extremely frequent in this patient population, often due to re-entrant pathways around surgical suture lines. These can often be treated with radiofrequency ablation while paying clos...
In the opening episode of the DeviceTalks podcast network's newest podcast, AbbottTalks, Dr. Christopher Piorkowski, Divisional VP and Chief Medical Officer of Electrophysiology, and Dr. Philip Adamson, Divisional VP and Chief Medical Officer of Heart Failure, discuss the significant advancements in Abbott's cardiac technology and their forward-looking approach to cardiovascular care. Piorkowski sheds light on the profound impact of technology on patient outcomes in AFib treatment and underscores the importance of enhanced risk stratification tools and personalized therapy approaches. Adamson delves into the progress of Abbott's HeartMate series, specifically the HeartMate 3, highlighting its improved performance and reduced complications compared to its predecessors. Both Abbott leaders stress the essential role of implementation science and foresee an upward trend in enhanced patient identification to administer therapies like the HeartMate 3, aiming to reach patients across the disease spectrum who could significantly benefit from these advanced therapies. Listen now to AbbottTalks' first episode, and make sure to subscribe on all major podcast platforms to get the behind-the-scenes look at Abbott's transformative work across its diverse portfolio. This episode is sponsored by Coatings2Go. For more information go to Coatings2Go.com. Thank you for listening to the AbbottTalks Podcast.
Ep 13: Battle of Heart Disease: Overcoming Obstacles with Armin MuzafirovicAgainst all odds, Armin refused to let his diagnosis define him. But a ski trip to Colorado brought an unexpected twist, changing everything he thought he knew about his condition. What happened next was an ongoing battle, and Armin's incredible resilience kept him fighting every step of the way.“In life, not everything is perfect, and sometimes we have obstacles that come our way...But being that rebellion that I was at 16, I didn't want to listen to healthcare providers. But as you physically see how your body is on the inside, when I saw my heart compared to a normal 17-year-old, I knew at that point that this is really serious.” - Armin.Bouba sits down with his guest Armin Muzafirovic to talk about the ups and downs of his heart journey. Armin has navigated the challenges of living with heart disease since his mid-teens. His journey began with a diagnosis of muscular dystrophy, followed by discovering his heart condition. Despite these setbacks, Armin has remained determined to live life to the fullest, continuously seeking activities that push the boundaries of his physical capabilities. Armin's story offers a unique perspective on the impact of heart disease on daily life and how he has adapted to his new reality.In this episode, learn more about:The complex world of heart transplant surgeries and the road to recovery.Uncover the crucial role of a support system in managing heart disease and treatment.Third, empower yourself as a patient advocate to take charge of your own heart health journey.Finally, understand the urgent need for organ donors and increase awareness about heart transplantation.Find out more about Armin here:Instagram: https://www.instagram.com/armin.muza/More from Living with Heart Disease:Episode 5 - Life with an LVAD while waiting for a heart transplantConnect with me: Instagram: livingwithheartdisease.podcastFacebook: https://www.facebook.com/heartofagiant.foundationYouTube: https://www.youtube.com/@heartofagiantTwitter: https://twitter.com/LWHDpodcastCatch the bonus content on our Youtube channel.https://www.youtube.com/@heartofagiantDid you enjoy this episode? A free way to support our show is by leaving it a rating and review on Apple Podcasts. It's a chance to tell us what you love about the show, and it helps others discover the Living with Heart Disease podcast. Apple Podcast https://podcasts.apple.com/us/podcast/episode-10-inspiring-journey-from-heart-failure-to/id1567454596?i=1000608329515Spotify https://open.spotify.com/show/4aJeFMvnXyazgGuhR8A4Xs?si=6d9f19949f514714&nd=1Chapter Summaries:[00:00:00] - Introduction,Bouba introduces the podcast and guest, Armin, a heart transplant recipient, and sets. The goal of the conversation is to understand a patient's perspective on living with heart disease.[00:03:13] - Initial Diagnosis,Armin discusses being diagnosed with heart failure in his mid to late teens, despite feeling healthy and athletic, and how it affected him and his plans for the future.[00:06:23] - Ski Trip Incident,Armin recounts a ski trip incident where he experienced shortness of breath, low oxygen, and a spike in troponin levels, leading to a mini heart attack and hospitalization. He also describes his symptoms of heart failure and the need for an ICD implant.[00:09:27] - Managing Heart Disease,Armin reveals his rebellious attitude towards being a heart patient, how he still played sports and lived life to the fullest despite his condition, and the importance of meeting strict criteria for treatments like pacemakers and ICDs.[00:13:12] - Medical Complications,Armin discusses the difficulties of managing heart disease, including the side effects of diuretics and the challenges of going to the ER for urinary problems. He also touches on the most prolonged surgery period during his ICD implant and the struggles of balancing school with frequent bathroom trips.[00:16:18] - Hospitalization and Online Learning,After being hospitalized for heart failure, Armin had to stay home due to edema and other symptoms. He had to call his school, where they had no prior experience with online learning. Armin managed to do his finals and pass with flying colors despite not being physically present for most of the classes.[00:23:05] - Overexertion and Passing Out,Armin passed out after overexerting himself while trying to pick up his brother from the bus stop. His feet were swollen due to edema. He fell unconscious and was shocked back by his ICD. He woke up in the hospital, and the doctors discovered that his leads were hitting his diaphragm.[00:26:17] - Tachycardia and LVAD Surgery: During a car ride to the hospital, Armin had 40-60 episodes of SVT tachycardia, a severe heart failure symptom. After arriving at the hospital, he had an emergency LVAD surgery due to his low ejection fraction, dangerously low at 15-20%.[00:29:27] - HeartMate 2 and RVAD,Armin had both an RVAD and LVAD implanted with the HeartMate 2. He spent 33 days in the hospital and used Doppler machines to check his pulse. He was grateful to be alive thanks to the LVAD, but he knew he had a long road ahead.[00:30:44] - Early Days with LVAD,The guest recalls his early days with LVAD and describes how he felt constantly monitored and disturbed in the ICU. He mentions the challenges of sleeping and eating in the hospital and highlights the warmth of the RVAD pumping blood out and in as a comforting experience.[00:35:45] - Delirium and Recovery,The guest talks about his delirium and the chemical imbalances in his body, making him feel like he was on fire. He recalls when he thought an X-ray technician was trying to kidnap him and how his mother had to change his dressing from the hospital until the heart transplant.[00:39:01] - Battery Life and Edema,The guest discusses how he had to be physically cautious with the LVAD and could not go anywhere because of the drive line. He highlights the importance of constantly charging the batteries and mentions the compression stockings he had to wear due to Edema.[00:41:21] - Dress Rehearsals and School,The guest mentions how he had to cancel school for the next two years because of his surgeries and describes the challenges of being in and out of the hospital every month due to Edema and potential calls for transplant. He talks about how he missed a full-ride scholarship due to his health condition.[00:43:15] - Donor Specific Antibodies,The guest recalls how he got a call at 2 AM about a potential heart and how he and his father drove[00:44:37] - Diuresis and Dry Weight,Armin discusses diuresis and reaching his dry weight before a potential heart transplant. He shares how he lost 40 pounds within a week and the toll it took on his body. He also talks about how he was bumped to 1A on the transplant list after getting a Milrinone 24-hour IV pump.[00:53:18] - Unexpected Shock,Armin recalls the time he was shocked twice by his ICD and how he was airlifted to a hospital. He shares how he got bombarded with Valentine's Day cards from nurses and how it brought a sense of humanity to his situation.[00:57:53] - Second Potential Heart,Armin talks about getting a second potential heart in March and going through all the necessary blood tests before going for the operation. He shares his excitement and hope for the future.[01:08:10] - Life after Heart Transplant,Armin discusses his recovery after the heart transplant, including physical therapy and medication. He shares how grateful he is to the donor and their family for giving him a second chance at life. He also talks about his plans for the future, including going to college and pursuing his dreams.[00:59:13] - Preparing for the Heart Transplant,Armin talks about getting ready for his heart transplant surgery, walking into the operating room, and the medical team preparing him for the procedure. He also talks about his previous surgeries and how he knew some of the nurses from before.[01:01:02] - The Long Surgery and Recovery,Armin talks about the length of his heart transplant surgery and the need for the transplant to be done quickly due to the time-sensitive nature of the procedure. He also talks about his recovery and his challenges post-surgery, including high white blood cell counts and fevers.[01:03:25] - Communicating After the Surgery,Armin talks about his communication with doctors and nurses after his heart transplant surgery. He explains that he used paper and a notepad to communicate, and he had certain doctors and nurses he preferred to share with.[01:06:22] - The Road to Discharge,Armin talks about his journey to discharge from the hospital after his heart transplant surgery. He discusses the importance of being safe and waiting for all testing to be completed before leaving the hospital. He also talks about his joy when he finally got home and saw his family. [01:11:07]- Gratitude and Support,Armin reflects on his heart transplant surgery and expresses gratitude for his family, healthcare providers, and EMS professionals who supported him throughout his journey. He talks about how important it is to have a support system during[01:13:19] - Importance of Support System,Armin emphasizes the critical role that a support system plays during the transplant process, particularly in managing emotions and medications. Having family and friends to cook meals and provide emotional support helped him through the difficult times. [01:18:30] - Staying Active After Transplant,Armin talks about the importance of staying active after the transplant and how he maintains his physical fitness through weight training and exercise. He also mentions the importance of balancing exercise with other aspects of life, such as work and school.[01:23:02]- COVID and the Transplant Games,Armin shares how he was training for the Transplant Games America in San Diego before contracting COVID-19. He planned to participate in track and field and basketball but had to cancel due to his illness. He remains hopeful for future games.[01:25:30]- Maintaining Mental Health,Armin stresses the importance of seeking help for maintaining mental health after a transplant. He recommends taking things one step at a time and staying organized, including breaking down tasks into smaller, more manageable pieces.[01:27:09] - In conclusion,Armin emphasizes the importance of maintaining physical and mental health after a transplant and encourages others to seek support from family, friends, and medical professionals. He stresses the need to stay positive and take things one step at a time.[01:27:49]- Why Share?Armin shares that as a former patient and future doctor, he understands the importance of advocating for oneself and others. He speaks about volunteering for his local organ procurement center and sharing his story at medical conferences to help educate and motivate patients.[01:29:06] - Taking Control,Armin emphasizes the importance of being one's advocate as a patient and understanding one's medical treatment. He encourages patients to speak up, share their insights, and take control of their health.[01:30:48]- Giving Back,Armin discusses his volunteer work at his local organ procurement center and speaks to patients waiting for transplants. He shares his insights and experiences to help others going through the same journey and inspires listeners to cherish each moment in life.[01:32:08]- Looking Ahead,Bouba and Armin discuss Armin's plans to become a doctor and continue advocating for patients. They express excitement for what's to come, and Bouba emphasizes the importance of sharing one's journey and experiences to inspire and motivate other patients and caregivers.[01:33:09] - Words of Wisdom,Armin shares his words of wisdom for patients and their caregivers, reminding them that they are not alone in their journey and encouraging them to cherish each moment, tell their loved ones they love them, and know their "why" in life.
Vidcast: https://youtu.be/-wEP9j8wqrU When the heart muscle begins to wear out and lose its life-supporting function but a transplant is not available or appropriate, an assist from a prosthetic pump is the only option to save a patient. Abbott's HeartMate 3 implantable pump has now been shown in the MOMENTUM 3 study of more than 1000 patients to effectively pump blood while not damaging it, a common complication of other models. The HeartMate's white glove blood handling and avoidance of stroke-producing blood clots is the result of using of magnetic forces to suspend the pump's rotor. The result: 58% of patients using the pump live 5 years or more. https://abbott.mediaroom.com/2022-08-29-New-Data-Show-Abbotts-HeartMate-3-TM-Heart-Pump-Extends-Life-Beyond-Five-Years-for-Advanced-Heart-Failure-Patients #heartfailure #abbott #lvad #stroke #clots
How's your marriage…I mean, really, how is it? Has the loss of a spouse closed your heart to meeting someone new? Does death or divorce make you feel that love is never available again? Does your long marriage (mine is 52 years) need a revitalizing kick? Have you been single for decades, and think that partnership has passed you by? Let me introduce you to Allana Pratt, The Intimacy Expert, www.allanaprat.com, and her new app, HEARTMATE.APP, Author of 6 bestsellers on intimacy, and Leading Couples and Relationship Coach DISCOVER: . Tools for love fulfillment .Why inner discovery leads to lasting relationships .Why dating services keep you solo . How to keep yourself open to new relationships while working through grief .Why you need you before you need anyone else Plus a love-giving exercise help celebrate Valentine's Day.
How's your marriage…I mean, really, how is it? Has the loss of a spouse closed your heart to meeting someone new? Does death or divorce make you feel that love is never available again? Does your long marriage (mine is 52 years) need a revitalizing kick? Have you been single for decades, and think that partnership has passed you by?Let me introduce you to Allana Pratt, The Intimacy Expert, www.allanaprat.com, and her new app, HEARTMATE.APP, Author of 6 bestsellers on intimacy, and Leading Couples and Relationship CoachDISCOVER:. Tools for love fulfillment.Why inner discovery leads to lasting relationships.Why dating services keep you solo. How to keep yourself open to new relationships while working through grief.Why you need you before you need anyone elsePlus a love-giving exercise help celebrate Valentine's Day.
In this episode, we'll dive deep into the Heart Failure business at Abbott. First we'll connect with Philip Adamson, MD, chief medical officer of the group. Dr. Adamson uses an explanation of CardioMEMS to give a vivid portrait of how patients live with heart failure. Technology, he says, makes turns those patients into their own health care workers. This podcast is sponsored by KNF. Then, we'll talk with Kevin Bourque, vice president of research and development, and Robert Kormos, division VP, global affairs of heart failure, about the advances of Heartmate 3. Both also detail how Abbott is working to help children suffering from the condition. Dr. Kormos also shares the most gratifying part of his job. The entire editorial staff joins the podcast to share their personal top stories of 2021. News includes mentions from Vicarious Surgical, ResMed, Philips, Pfizer, BioNTech, Abbott, Dexcom and Insulet. Happy New Year!!! We'll see you in 2022. LIKE! FOLLOW! SUBSCRIBE!
This week's episode features special Guest Host Mercedes Carnethon, as she interviews author Sung-Min Cho and Associate Editor Marc Ruel as they discuss the article "Cerebrovascular Events in Patients with Centrifugal-Flow Left Ventricular Assist Devices: A Propensity Score Matched Analysis from the Intermacs Registry." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to look at centrifugal flow, left ventricular assist devices and cerebrovascular events. But before we get to the feature, how about we grab a cup of coffee and jump into some of the other articles in the issue? And maybe how about I go first? Dr. Carolyn Lam: All right. I got my coffee. Dr. Greg Hundley: So my first paper comes from Professor Dali Luo from Capital Medical University. And it's pertaining to calsequestrin-1. So calsequestrin-1, and calsequestrin-2 isoforms buffer calcium and regulate its release from the sarcoplasmic reticulum of skeletal and cardiac muscle. Human inherited diseases associated with mutations of calsequestrin-1 or 2 include malignant hyperthermia and environmental heat stroke and catecholamingergic polymorphic ventricular tachycardia. However, patients with hypothermia, environmental heat stroke events often suffer from an arrhythmia for which the underlying mechanism remains unknown. Dr. Carolyn Lam: Wow. Okay. And what did the current paper do and find? Dr. Greg Hundley: Great, Carolyn. So what the authors found, calsequestrin-1, the skeletal isoform of it is indeed expressed in cardiomyocyte sarcoplasmic reticulum for mirroring in human hearts, mostly presenting as a polymeric form and interacting with the ryanodine 2 receptor in ventricles. Second, calsequestrin-1 deficiency cause sinus tachycardia in basal conditions. And this is a novel finding which may be associated with sinus beat regulation and ventricular arrhythmia as an independent arrhythmogenesis if a high concentration of volatile anesthetics are used. Next, these volatile anesthetics and heating to 41 degrees C can directly induce calsequestrin-1 oligomerization, thereby causing enhancement of diastolic calcium leak and premature calcium transience through a reduced regulatory effect of calsequestrin-1 on ryanodine 2 activity. And so Carolyn, this novel mechanism underlying the arrhythmia occurring in patients with malignant hypothermia or environmental heatstroke episodes may provide different strategies for heart disorders as an independent profile in these syndromes. And finally, the finding of calsequestrin-1 confirmational change induced by triggers in those with malignant hyperthermia and environmental heatstroke could lead to novel therapeutic approaches to prevent these types of episodes. And that may also very, very useful in treatment of heatstroke. Dr. Carolyn Lam: Wow. Thanks Greg. Well, moving from this preclinical world to a very common clinical question of the diagnosis of acute myocardial infarction. Now we know that in patients presenting to the emergency department with symptoms suggestive of an MI, the European Society of Cardiology zero and one hour algorithm is recommended by current ESC NSTEMI guidelines with a class one recommendation. Now, what this does is it combines a very high safety for early rule-out and high accuracy for rule-in allowing a definite triage of about 70 to 75% of patients using the zero in one hour sample. Dr. Carolyn Lam: However, what is the most appropriate management of the 25 to 30% of patients who remain in the gray observed zone? So this is the question that the current paper addresses. Now to answer this, we also need some more background that a single center pilot study previously of patients in the observed zone had derived a cutoff of seven nanograms per liter for a zero and three hour high sensitivity cardiac troponin T change to identify patients also eligible for early rule-out or rule-in of NSTEMI. So the current study that we're talking about in today's issue from Dr. Christian Mueller from Cardiovascular Research Institute in Basil, Switzerland, and colleagues, really aimed to externally validate that previously proposed seven nanogram per liter change cutoff, and if necessary derive and internally as well as externally validate some new criteria for these patients in the observed zone of the ESC zero in one hour algorithm. Dr. Greg Hundley: Wow, Carolyn, so we're learning a lot about cutoff values and also algorithms here with high sensitivity cardiac troponin T. So what did they find here? Very interested to hear. Dr. Carolyn Lam: So in two large prospective multicenter diagnostic studies, they found that the proposed zero and three hour high sensitivity cardiac troponin T change of seven nanogram criteria, unfortunately provided suboptimal safety for ruling out NSTEMI in patients remaining in the observed zone of the ESC zero and one hour algorithm. So this had a sensitivity of only 33% and missed 80 patients with NSTEMI. So they derived their own novel criteria based on zero and three hour samples. And these novel criteria combined a three hour high sensitivity cardiac troponin T concentration of less than 15 nanograms per liter and a zero and three hour absolute change cutoff of four nanograms per liter. Dr. Carolyn Lam: And that combination provided a high safety for ruling out NSTEMI in these patients in the observed zone and with a sensitivity of 99% missing only one patient with NSTEMI. Another further thing they found was at a zero and three hour cardiac troponin T absolute change of greater or equal to six nanograms per liter triage, 63 patients, or 11% towards rule-in thus resulting in a specificity of 98%. So in summary, this novel criteria based on zero and three hour sample seemed to balance safety and efficacy well for the further decision making in patients who are remaining in the observed zone after the zero and one hour cardiac troponin T algorithm. Internal validation of these novel criteria and external validation in an independent international cohort showed robustness of performance metrics and further strengthen its possible clinical use. Dr. Greg Hundley: Very nice, Carolyn. Lots of data there, and hopefully very important clarification on both the zones as well as the cutoff values for using cardiac troponin T. Well, Carolyn, my next paper again comes from the preclinical science world and it's from Dr. Anne Eichmann at Yale University School of Medicine, and it pertains to activin receptor-like kinase 1. And we're going to call that ALK1. Dr. Greg Hundley: Kinase 1 and we're going to call that ALK1. And it's an endothelial transmenbrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. And loss of function mutations of the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasias, a devastating disorder that leads to arteriovenous malformations. Dr. Carolyn Lam: Oh, okay. And what did the authors find? Dr. Greg Hundley: Dr. Carolyn Lam, ALK1 mutants displayed defective polarization against the direction of blood flow in capillary and venous endothelium as well as increased integran VEGF receptor 2 mediated P13K activation of YAP/TAZ signaling. Dr Carolyn Lam: Okay, Greg, that was super summarized but what are the clinical implications? Dr. Greg Hundley: Carolyn, pharmacological integrin inhibition using cilengitide or ATN-161, or YAP/TAZ inhibition using verteporfin, prevented AVM malformation in ALK1 mutant mice. And therefore for this study, the authors revealed that integrin and YAP/TAZ were novel affectors of ALK1 signaling in AVM pathogenesis that might be targeted for AVM treatment in patients with hemorrhagic telangiectasias. Dr. Carolyn Lam: Thank you, Greg. Well, let's review what else is in today's issue. There's an exchange of letters between Doctors Amadio and Valentine on cell-free DNA to detect heart allograph acute rejection. There's an AHA Update paper by Dr. Churchwell on preemption, a threat to building healthy, equitable communities. There's a Research Letter by Dr. Merkler on the association between cervical artery dissection and aortic dissection. Dr. Greg Hundley: And Carolyn, I've got a paper from Professor Daniels regarding the Clinical Implications of Basic Research getting inside the engine, the myosin modulation of hypertrophic cardiomyopathy and systolic heart failure. And then finally, there's an In Depth piece from Dr. Viskin entitled, “Polymorphic Ventricular Tachycardia: The Terminology, mechanism, diagnosis and Emergency Therapy.” Dr. Carolyn Lam: Nice. Well, let's go on to our feature discussion. Can't wait. Dr. Greg Hundley: You bet. Dr. Mercedes Carnethon: Welcome to this episode of Circulation on the Run, our podcast where we have an opportunity to talk with the authors of some of the top articles within our journal for a given week. And we've chosen today to focus on a set of articles, one of which is led by Dr. Sung-Min Cho from the Johns Hopkins University. And I'm really excited to have you with us today, Dr. Cho and joining us as well as the associate editor, Dr. Marc Ruel who handled the paper. And my name is Mercedes Carnethon from the Northwestern University's Feinberg School of Medicine. I guess without further ado, welcome to you both and we'll just jump right into it. Dr. Mercedes Carnethon: Dr. Cho, I'd love to hear a little bit more about your paper today. What made you choose to pursue this particular topic and what really inspired you? Dr. Sung-Min Cho: Thank you so much for the invitation and opportunity to talk today. During my training as a neuro person, I'm a neurointensivist by training and neurologist. I noticed that we are getting a lot of consults for LVAD associated strokes. When I took a closer look at the ENDURANCE trial, very showed really 29.7% stroke rate at two years and a few years later, we had this MOMENTUM 3 trial, which showed HeartMate 3 device had 10% stroke rate at two years. And we realized that a stroke is a major issue in this population and I wanted to study the incidence respecters and outcome of this strokes in LVAD population. However, despite the many observational studies in the past, we were really interested in looking at device specific stroke risk for current continuous flow LVADs and we wanted to look at the device specific risk and prevalence of these patients balancing co-morbidities each cohort. And that's why we conducted this study. Dr. Mercedes Carnethon: Great, well Sung-Min, it's not often that as an epidemiologist and cardiovascular epidemiologist that I actually get to talk with neurointensivists and get their insights on the importance of their work. Can you tell me a little bit about what you found and whether it surprised you? Dr. Sung-Min Cho: Population, we used the Intermacs registry database. This is well established database as all cardiologists and cardiothoracic surgeons know, and we defined a neurologic adverse event as stroke plus TIA, transient ischemic attack. We used a propensity score matching analysis to assess the association of HVAD with stroke risk, to balance for pre-implant risk factors. And basically after performing propensity score matching, we found that hazard of stroke was higher for patients with HVAD device compared to HeartMate 3. We kind of expected this based on the randomized control trials in the past but there was no head to head comparison between these two cohorts. This study really confirmed our suspicion that HeartMate 3 actually had lower hazard of a stroke compared to HeartMate 3. Dr. Mercedes Carnethon: Well, thank you so much. It's a really great explanation. And for those who haven't had a chance to dig into the issue yet, I really encourage you to read the piece. I found it to be very instructive. And I'm interested as well, Mark in your take about what excited you about this piece. Dr. Marc Ruel: Well, thank you very much Mercedes and Sung-Min it's really a pleasure to have you with us today. As you know, this has been a very impactful paper and you were very kind to share with us the study around your idea as to why you wanted to evaluate this question but even more than your idea and what led to the completion of the paper are the implications of your paper. And I think it would be great if you shared with us a little bit, what has been the path that your paper has led to and including amongst others, very likely a decision by the Medtronic to pull the HVAD out of market. It's interesting that your data, to my knowledge, correct me if I'm wrong, were presented first at the annual meeting of the Society of Thoracic Surgeons in January, 2021. And again, I want to reiterate that Circulation's very thankful that you chose to send your paper to our journal and we feel that it will give it full justice, like many other journals of would have had but we're really excited to have received your paper and give it the fullest consideration. Dr. Marc Ruel: Can you tell us a little bit about the implications and for lack of a better word, the storm that your paper has created in the field and your take on it? Dr. Sung-Min Cho: Right. That's a great question. Thank you for that. Like I said, as a neurologist, we see these patients after complication, patients having stroke and then we see these patients and we always wanted, cardiologists and cardiothoracic surgeons and neurologists, we always wondered which device carried more risk for stroke and TIA. And really our group actually worked on many papers in the past looking at single institutional data and also systematic review meta-analysis looking at this topic, but really HeartMate 3 came along a couple years ago, more recent device so we didn't have a lot of data. Dr. Sung-Min Cho: So intermex registry really helped since we didn't have a lot of data. So, INTERMACS Registry really provided opportunity for us to look at this specific question, really balancing those two chords to look at the risk of stroke in this HeartMate 3 and HVAD. And when we did that two years ago, we submitted a proposal to INTERMACS, and Dr. Kirklin from UAB, he really helped us to look at this data closely with his statistical team. And we had really a thorough statistical method to perform a propensity matching analysis. And we finally finished the analysis and presented in annual STS meeting in January, and it did really trigger a lot of attention to a lot of academic institutions and people who are practicing LVAD, and after that, when we finally submitted this paper to Circulation, we had to have a lot of discussion in between FDA and the Medtronic and discussing this implication of this paper. When it was finally published in Circulation, we are happy that there's a lot of attention and we made it through. Dr. Marc Ruel: Well, thank you, Dr. Cho, and maybe for the listener of this podcast, I would like to reiterate some of the salient points of your paper essentially, and correct me if I'm wrong, over 6,200 patients were included, about roughly 3,000 patients per group comparing the HeartMate 3 versus the HVAD. Dr. Marc Ruel: Now, as you alluded to the HVAD is the more ancient device, if you will. So there's a slightly longer follow-up, around 12 months on median, versus nine months with the HeartMate 3. And there's adjustment that has been made for this. And I think to me, really the key finding is that in the early acute phase around implantation, there is no real difference with regards to the risk adjusted incidents of neuro adverse events. However, once you pass the early implantation acute phase, in the chronic stable phase, there starts being really a signal that is detrimental to the performance of the HVAD versus the HeartMate 3. And I think your hazard ratio, correct me if I'm wrong, it's around 5.7 for neuro adverse events. Dr. Marc Ruel: So this is a very compelling hazard ratio, even coming out of an observational study with all the careful attention that you provided to adjust for residual confounding, et cetera. Dr. Marc Ruel: So obviously this is a very strong finding, but I would like you to perhaps comment on this, the patients are not the same. There's some indication that the HVAD patients may have been a little sicker, more RV dysfunction, more tricuspid regurgitation, higher INTERMACS-1 incidents more often on ECMO prior to an implant. What are your thoughts about this? Dr. Marc Ruel: Obviously, you've been very careful and the reader will note in the paper that many attempts have been made to account for those. But please give us your take around that 5.7 hazard ratio for neuro adverse event that you found. Dr. Sung-Min Cho: Right? In fact, we were really being careful adjusting those compounders. So we did a propensity matching has a primary analysis, but as you pointed out, as a secondary analysis, we wanted to look at multi-variable logistic regression analysis, looking at multi-hazard analytics. And when we did the secondary analysis, as you said, in the beginning early hazard period, the risk was similar, as time went on in the constant hazard period, the hazard ratio was 5.7 for HVAD compared to HeartMate 3, which gives a much higher risk of stroke and TIA for those patients with HVAD compared to HeartMate 3. Dr. Sung-Min Cho: So, that was really convincing to us. Confirming the findings from propensity matching analysis, showing that same findings were consistent throughout the different analysis. As we pointed out, HVAD patients actually were sicker, they had more ECMO, and they had more ventilation requirement or sicker patients INTERMACS level. Those are all carefully balanced in both propensity matching analysis and also multi-hazard analytics. And both of these analysis consistently showed that HVAD carried more risk of TIA and stroke compared to patients with HeartMate 3. Dr. Mercedes Carnethon: Thank you so much Sung-Min. You know what excites me as I think about choosing articles for journal clubs, when we're working with our trainees, the propensity matched approach and comparing it directly with what you're getting from multi-variable regression really provides an excellent methodological strategy to be able to generate results from these real world studies where it's not a randomized trial of who received which device, but we're able to yield practical conclusions that are actionable based on these findings when we have these well done analyses. And Marc alluded earlier to the actions that were taken in response to the findings from your study. Can you expand on those just a little bit more? Sung-Min Cho: Of course. So I guess, I don't know the real backstory, what was going on behind the scene, but I know for sure that STS leadership and INTERMACS leadership, they had a lot of discussion with the company who made HVAD device and also FDA, and I know that this study, the results of this study contributed to the decision they made back in June, pulling up HVAD device from the market. Sung-Min Cho: So I'm glad that this study could contribute to the science and hopefully this will help the patients in the future for device selection. So yeah. Dr. Marc Ruel: Sung-Min, I think it's fair to say that your study is probably, if not the most impactful in the field of ventricular assist devices, and I probably would personally think that it is, if not the single most impactful, certainly one of the two or three that are the most impactful. So congratulations to you and your team. Dr. Marc Ruel: If you still have a minute or two, I had a couple of more secondary questions? Dr. Marc Ruel In your analysis I noted that in the early acute phase, there are some protective predictors, such as performing the LVAD implant by sternotomy, which essentially results in about half of the neuro adverse events that you would otherwise observe. So I was a little intrigued by that. And high volume centers had about 1.8 hazard ratio. I suspect that's probably reflective of baseline risk and more acute illness in those patients coming. But if you have a chance, I'd love to hear your thoughts around this? Dr. Sung-Min Cho: Yeah, that's exactly what we thought actually is, initially we thought, hypothesized that surgical volume, the center volume will be associated with lower risk of stroke, but it was the other way around. But as you said, probably higher volume centers were getting sicker patients, so that's the association probably we were getting in the analysis. And we wanted to adjust for surgical techniques, sternotomy versus thoracotomy, and even after adjusting for that, HVAD remained a significant hazard per stroke, which showed in the table two and three, I think in the manuscript. Dr. Sung-Min Cho: And if I may, I want to say these couple of things. In the raw number, in the 6.4% of patients actually had TIA and strokes, neurological adverse events in HeartMate 3, at one year based on our study. And the risk goes up with a longer follow-up time of course. Moment3 trials had two-year follow-up, about 10% had stroke. And this is still, after HVAD is taken off the market, still there's a significant risk for stroke in these patients and based on autopsy and MRI studies although there is a very small studies--MRI studies, although they're a very small series, studies looking at MRI'd brains after explantation of LVAD. And it shows actually more than 95% of patients have cerebral micro bleeds, which is a marker for small vessel disease in the brain. I think this is an important issue, and although we show that one device had a lower risk of stroke, still question remains, are these patients have a high risk of stroke? And there is a need for improving biomedical engineering aspect, and I'm sure cardiologists and cardiothoracic surgeons know much better than I do regarding hemo-compatibility, especially for stroke. Dr. Sung-Min Cho: There is also a dire need for early detection and intervention for these events to improve the outcome for these patients, because once you have a stroke, the outcome is devastating, right? So I think there needs to be better medical management, neuroprotective agent, as well as neuro- monitoring methods, maybe biomarkers to predict stroke or TIA to come so we can intervene and prevent these really devastating complications. Dr. Marc Ruel: Mercedes, if I'm so allowed, I do have one final comment and question. Dr. Mercedes Carnethon: Most definitely. This has been delightful, so yes. Dr. Marc Ruel: Wonderful. So, first, Sung-Min, I want to thank you for working with us. We at Circulation were interested in your paper. You may recall you and I spoke on the phone offline when the decision to revise was made, and we went carefully over what the editors were anticipating would make your paper even better. And you were very responsive. You and your co-author's team were tremendous. And I think the paper that we have before us is absolutely very, very insightful and very important. And obviously tremendously impactful. So I want to thank you again for that. Dr. Marc Ruel: And my question is probably the very difficult question which is in everybody's mind at this point and I would like your take as a neurointensivist. You have someone who you have to care for who has a well-functioning HVAD, two years post implant. What would you recommend in terms of optimization for the prevention of neural adverse events? I realize we don't have all the information, but you are one of the few experts in the world who can probably provide us with a very valid take on this very difficult question. Dr. Sung-Min Cho: Yeah, it is indeed a difficult question. And that's what I am, including me a lot of neurointensivists, they are very interested in this topic. I think really, as I alluded before, only detection is really important, but it's really tough because either patients, they cannot get MRI. There's no way to know who's going to have stroke or not. Dr. Sung-Min Cho: We know that a bacteremia is a huge risk factor for these patients. Whenever they have device infection, dry valve infection, bacteremia, their stroke risk goes up quite a bit. We have a lot of data on that. So we can carefully monitor these patients, follow these patients. There is some data that, within six days from infection, their stroke risk goes quite high up for these patients. Dr. Sung-Min Cho: But really, neuro-monitoring and biomarker study, there's so little data on this, but patients who are sick like this, not just LVAD patients but ECMO patients or ICU patients, are close neurologic monitoring and some markers to predict occurrence of a stroke or vascular event. I think that's something we really need to study and look into. Dr. Sung-Min Cho: Of course, we have a lot of biomarkers we can pick up from the brain, brain injury markers that we can study, and that has not been done in this space. And there are a lot of opportunities, I think, to look at that. And there's some signal based on Cleveland Clinic data that Randall Starling actually looked into, use of PDE5 inhibitor in this patient population, some protection against the ischemic stroke, and I think that's something also we should look into for neuroprotective agent. Dr. Mercedes Carnethon: Thank you so much! This has been such a delightful discussion this morning with Sung-Min Cho, the lead author of the study and the Associate Editor, Marc Ruel who handled it. Dr. Mercedes Carnethon: I really appreciate your attention. I hope the listeners enjoyed this episode of Circulation on the Run. Please join us again next time. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
Přes 200 zachráněných nebo alespoň prodloužených životů - to je výsledek sedmiletého trvání programu umělých srdečních podpor HeartMate 3 v Institutu klinické a experimentální medicíny. Jiné druhy srdečních podpor se v IKEM používají už od roku 2003. Dlouhodobá srdeční podpora, tedy přístroj voperovaný přímo do srdce pacienta, umožňuje žít i pacientům, kteří jsou třeba kvůli vyššímu věku nebo prodělanému onkologickému onemocnění nevhodní jako kandidáti pro transplantaci srdce. Více v rámci IKEM Podcast prozradil prof. Ivan Netuka, přednosta Kliniky kardiovaskulární chirurgie IKEM.
In today's episode, Deidre will be talking to her soul sister Allana Pratt, the go-to authority for those who have suffered from heartbreak and are ready to live unapologetically and attract open-hearted relationships.Along with being an Ivy League graduate, she is also the author of six books and hosts a podcast called Intimate Conversations. Allana has been featured in the Huffington Post, Forbes, People Magazine, CBS, FOX, The Jenny McCartney Show and is a columnist for the Good Men Project. This woman is truly amazing.With over 5 million viewers on Youtube, Allana is a certified coach who offers private group and online coaching for singles and couples. She helps her clients develop healthy and intimate relationships with themselves, which allows them to attract their ideal partnerships.Join me in today's episode as we discuss her book From Heartbreak to Heartmates and discover the truth about lockdown love, and by doing the work, you can learn how to have a relationship that changes the world.Highlights from this week's episode:What is lockdown love?How to love yourself and how to fully get there?How to know if you are rejecting yourself and not knowing you're doing itWhat does it mean to be in your pussy, and how does one get there?In the space of dating, what are things to look out for in-person and onlineBeing your best selfHow to open up to yourself when naturally we always think we're fineHow to practice loving yourselfTo learn more about Allana, be sure to visit her website at Alanapratt.com. On her site, you will be able to take her blind spot assessment quiz, listen to her cuddle puddle webinar for free, and find all six of her books, including Heartbreak to Heartmates.Now, if you're somebody who has tried online dating apps and still struggling to make a connection with someone, visit Alana's Heartmate.app, where singles learn to become one, find the one, and keep the one.Connect with Allana Pratt:Podcast: Intimate ConversationsYouTube Channel: @Allana PrattInstagram @AllanaPrattFacebook @Allana PrattConnect with Deidre Sirianni:Instagram: @deidresirianniFacebook Group: @radicallyalignedWebsite: www.radicallyaligned.comYouTube: @deidresirianniTEDx Unhealed Trauma - The Root Cause Of All SufferingLinkedIn: @deidresirianniEmail: hello@radicallyaligned.com
JHLT: The Podcast is back for its third round table talks. Daniel R. Goldstein, MD, Editor-in-Chief of the Journal of Heart and Lung Transplantation, leads a discussion with the JHLT Digital Media Editors focusing on topics from the March issue of JHLT. Starting at 2:05, David Schibilsky, MD, and Van-Khue Ton, MD, PhD, discuss an MCS paper from Dr. McGiffin and colleagues in Melbourne, Australia, titled “The results of a single-center experience with HeartMate 3 in a biventricular configuration.” Starting at 14:00, Erika Lease, MD, and Marty Tam, MD, discuss a study from Benke and colleagues in Budapest, Hungary, called “Methane supplementation improves graft function in experimental heart transplantation.” Follow along in the March issue at www.jhltonline.org/current. 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.com.
In this Giants of Cardiothoracic Surgery interview, Joel Dunning speaks with Oscar Howard “Bud” Frazier about his career. Dr Frazier trained with Michael DeBakey and Denton Cooley while they were developing the first mechanical heart. He continued and advanced this work throughout his career while also performing over 1,200 heart transplants and over 500 left ventricular assist devices (LVAD). Dr Frazier also performed the first HeartMate implantation and the first Jarvik implantation. He has been an instrumental part of mechanical heart development and continues to take a close interest in this rapidly advancing field.
This week’s episode features author Emma Birks and Associate Editor Hesham Sadek as they discuss the article " Prospective Multicentre Study of Myocardial Recovery Using Left Ventricular Assist Devices (REmission from Stage D Heart Failure: RESTAGE-HF): Medium Term and Primary Endpoint Results." TRANSCRIPT BELOW: Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center of VCU Health in Richmond, Virginia. Carolyn, our feature article this week, we're going to examine myocardial recovery using left ventricular assist devices, getting some early results from the RESTAGE-HF study. But before we jump to the feature discussion, how about we discuss some of the papers in the issue? Would you like to go first? Dr. Carolyn Lam: Yes I would. Have you thought about what's the benefit of emergent coronary angiography after resuscitation from out of hospital cardiac arrest for patients without ST elevation? It's an important question. Well, the portal study was reported by Dr. Kern from University of Arizona and colleagues, and this was designed to evaluate the efficacy and safety of early coronary angiography and to determine the prevalence of acute coronary occlusion in resuscitated out of hospital cardiac arrest in patients without ST elevation. So adult comatose survivors without ST elevation after resuscitation, were prospectively randomized to early coronary angiography versus no early coronary angiography, where early was defined as less than 120 minutes from arrival at the PCI capable facility. The primary endpoint was a composite of efficacy and safety measures, including efficacy parameters of survival to discharge favorable neurological status at discharge echo measures of left ventricular ejection fraction, more than 50% and a normal regional wall motion score within 24 hours of admission. Dr. Greg Hundley: So, lots of data here. What did they find? Dr. Carolyn Lam: So, unfortunately the study was prematurely terminated before enrolling the target numbers of patients. A total of 99 patients were enrolled from 2015 to 2018 and 49 were randomized to early coronary angiography. The primary endpoint of efficacy and safety was not different between the two groups. Early coronary angiography was not associated with any significant increase in survival or adverse events. And early coronary angiography revealed a culprit vessel in 47% with a total of 14% of patients undergoing early coronary angiography, having an acutely occluded culprit coronary artery. So while this was an underpowered study, when considered together with previous clinical trials, it does not support early coronary angiography, comatose survivors of cardiac arrest without ST elevation, whether early detection of occluded potential culprit arteries leads to interventions that improve outcomes does require additional study. And this is discussed in an editorial by Dr. Lemkes from Amsterdam university medical center. Dr. Greg Hundley: Very nice Carolyn. So at least the study that points us toward the next study that has to be performed and also does with other studies provide a little more clarity. Well, my next paper is from Professor Sanjiv Shah and--oh, wait a minute! And also from you as a co-author. Well, Carolyn, how about we have a little mini feature discussion where I can ask you some questions and then you can tell us all about your paper. Dr. Carolyn Lam: Happy to. Dr. Greg Hundley: Great. So Carolyn, what hypotheses were you testing and what was your study design and who was included in your study population? Dr. Carolyn Lam: Okay. So the question was we wanted to answer was thus a systemic pro-inflammatory state as indicated by proteomic profiling. Does that mediate the association between comorbidities and normal cardiac structure and function in HFpEF. To answer that we studied 228 patients with HFpEF from our multicenter promis HFpEF study. And these patients had 248 unique circulating proteins quantified using the old link multiplex immunoassay. Now I'm going to describe a complex analysis, but we basically had to first perform principal component analysis. And we did this to summarize 47 proteins known a priori to be involved in inflammation, and then used unbiased network analysis of all the 248 proteins to identify clusters of proteins that over-represented inflammatory pathways. We then used a mediation analysis to determine whether and to what extent inflammation mediates the association of comorbidity burdens with abnormal cardiac structure and function. And finally, we externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without HFpEF. Dr. Greg Hundley: Wow Carolyn, such a great design and an app machine learning mediation analyses, and then validation in an independent cohort. So tell us, what did you find? Dr. Carolyn Lam: So first, comorbidity burden was associated with abnormal cardiac function and structure and with these principle components of clusters of inflammation proteins. Second, systemic inflammation was associated with echo indicators of worse hemodynamics, like higher EDE' ratio and worse, right ventricular function. And third, inflammation indeed mediated the association between comorbidity burden and many of these echo parameters with, and I'm going to name a couple of routines. So TNF-R1, uPAR, IGFBP-7 and GDF-15 being the top individual mediating proteins. In the validation cohort inflammation was up-regulated in HFpEF compared to controls and the most prominent inflammation protein cluster identified was also the same one as in PROMIS-HFpEF. Dr. Greg Hundley: Beautiful Carolyn. So with these new proteins identified, what's the take home message here? Dr. Carolyn Lam: Here it is. Proteins involved in inflammation form a conserved network in HFpEF. And this was found across two independent cohorts. This may mediate the association between comorbidity burden and echo indicators of worst hemodynamics and right ventricular dysfunction. In totality, these findings support the comorbidity inflammation paradigm in HFpEF. Dr. Greg Hundley: Great job Carolyn, I liked the mini feature. That was so nice having one of the authors of the study here to explain kind of a two for one here, because we're going to get a feature and a mini feature. Have you got another paper you want to tell us about? Dr. Carolyn Lam: Thanks Greg and that works both ways. This next paper provides insights into the identity origin and function of many cells that make up late stage atherosclerotic lesions. It also identifies the mechanisms by which these control plucks stability. So corresponding author, Dr. Owens from Virginia School of Medicine and colleagues conducted a comprehensive single cell RNA sequencing of advanced human carotid endarterectomy samples, and compared these with murine micro dissected advanced atherosclerotic lesions with smooth muscle cell and endothelial lineage tracing to survey all plaque cell types and to rigorously determine their origins. Dr. Greg Hundley: Carolyn you know, this is another great study where we have both human subjects research and small animals. What were their results? Dr. Carolyn Lam: They provided evidence that smooth muscle cell specific knockout of transcription factors, KLF4 versus Oct-4 showed virtually opposite genomic signatures and their putative target genes played an important role, regulating smooth muscle cells phenotypic changes. They also provided evidence that smooth muscle cell derived cells within advanced mouse and human atherosclerotic lesions exhibited far greater phenotypic plasticity than generally believed, with KLF4 regulating the transition to multiple phenotypes, including LGALS 3 plus osteogenic cells likely to be detrimental for late stage atherosclerosis plaque pathogenesis. So in summary, smooth cell phenotypic switching produces cells that can be beneficial or detrimental to lesion stability and may be an important mechanism controlling the risk of unstable atherosclerotic plaque and myocardial infarction or stroke. Dr. Greg Hundley: Oh, great job, Carolyn. Well, the next paper I have is from Professor Muredach Reilly from Columbia University. And Carolyn smooth muscle cells play significant roles in atherosclerosis via phenotypic switching, a pathological process and with smooth muscle cell D differentiation, migration and trans differentiation into other cell types yet how smooth muscle cells contribute completely to the pathophysiology of atherosclerosis remain somewhat illicit. So the authors sought to reveal the trajectories of smooth muscle cell trans differentiation during atherosclerosis, and to identify molecular targets for disease therapy by combining smooth muscle cell fate mapping and single cell RNA sequencing of both mouse and human atherosclerotic plaques. Dr. Carolyn Lam: Echoing what you said earlier, Greg, both animal and human data. Terrific. So what were the results? Dr. Greg Hundley: The authors found that smooth muscle cells transitioned to an intermediate cell state during atherosclerosis, which was also found in human atherosclerotic plaques of carotid and coronary arteries. Smooth muscle cell derived intermediate cells termed stem cells were multiphoton and could differentiate into macrophage like and fibro chondrocyte like cells as well as returned towards the smooth muscle cell phenotype. Retinoic acid signaling was identified as a regulator of the transition of smooth muscle cells to stem cells and RA signaling was dysregulated in symptomatic human atherosclerosis. Finally Carolyn, human genomics revealed enrichment of genome-wide association study signals for coronary artery disease in RA signaling target gene low PSI and correlated between coronary artery disease risk levels and repressed expression of these genes. Now, activation of RA signaling by all trans retinoic acid and the anticancer drug for acute promyelocytic leukemia blocked the smooth muscle cell transition to stem cells, and that also reduced atherosclerotic burden and then promoted fibrous cap stability. So a lot of clarification of the role of smooth muscle cells, trans differentiation and the development of atherosclerotic disease Dr. Carolyn Lam: Indeed and translational implications. Interesting. Now let's review some of the other papers in this issue. Shall we? First as an, on my mind paper by Dr. Kullo on familial hypercholesterolemia, a reportable disorder. There's an exchange of letters between doctors Lazzerini and Li regarding the article autoantibody signature in cardiac arrest. Dr. Greg Hundley: Thanks Carolyn. Well, I've got a couple other papers to tell you about really a series of research letters from the mailbag. So first Daniel Modin has a Research Letter entitled “Acute COVID-19 and the Incidents of Ischemic Stroke and Acute Myocardial Infarction.” Dr. Christian Mueller has a Research Letter entitled “Effect of a Proposed Modification of the Type 1 and Type 2 Myocardial Infarction Definitions on Incidents and Prognosis.” And finally Carolyn a Research letter from Dr. Jizheng Wang involving an East Asian-specific common variant in TNNI3 that appears to predispose to hypertrophic cardiomyopathy. Well, Carolyn, what a great issue and thank you for that many feature, but how about we proceed on next to our feature discussion? Dr. Carolyn Lam: Let's go, Greg. Today's feature paper is one of those that I think is going to change clinical practice. So please listen up. It's about the RESTAGE-HF study. So pleased to have with us the first and corresponding author, Dr. Emma Birks from University of Kentucky Gill Heart and Vascular Institute, as well as our associate editor, Dr. Hesham Sadek from UT Southwestern to discuss this very important paper. Emma, could you please describe the RESTAGE heart failure study? Dr. Emma Birks: Let's say prospective study of patients getting left ventricular assist devices. So patients with very advanced heart failure are receiving left ventricular assist devices as either a bridge to transplant or as destination therapy. And they're seeing them for chronic heart failure because really all other medical therapy has failed and we use the pump to try and recover their own heart. So when the pump's implanted, we optimize the LVAD unloading, the maximum loading, and we give them a very aggressive medical therapy regime, unless they may not have tolerated these medications before because of poor blood pressure and renal dysfunction, we find they do tolerate them. So we give them in very aggressive doses and then we monitor their underlying function at regular intervals and try and promote recovery. So with that, we had done this in England in the past, in a single center study, but it had not yet been reproduced, which was obviously essential to have a bigger impact. Dr. Emma Birks: So we did a prospective study of six big US centers. We found that we've created a primary endpoint that was statistically powered in advance. And the primary endpoint was the number of patients that recovered within an 18 month period, that were explanted and remained off the pump and alive without transplant over for one year. So overall we found that of the 40 patients we recruited in the centers with chronic heart failure, we were able to explore 19. Of those that satisfied the primary endpoint, that was actually 40% of patients, with 52.3% being explanted overall. And importantly, patients were explanted in all six centers, so we found that the protocol was reproducible under the how much higher rate of recovery that you would otherwise see. Normally there is a database in the US that tracks outcomes from bad patients. And generally only 1-2% seemed to recover enough to be explanted generally. So this was a much bigger percentage. Dr. Carolyn Lam: Emma, first of all, congratulations, what an important trial and what stunning results. More than half of patients receiving that protocol were explanted. That's just remarkable. Now, could I just ask, what is it that you did that was different? I noticed you spent a lot of time saying this was an aggressive pharmacological protocol that was along with the LVAD unloading. Could you maybe elaborate on that a little bit more? Dr. Emma Birks: Yeah, I think that was a very important part of it. So generally I think when the LVAD goes in most centers, the patients are very sick, so most of those patients wouldn't then try and recover them or look at underlying functions. I think that was the first thing that was different was to try very hard. And then we had centers, the experience, I had done this before, it was also very helpful, all agreeing to do the same thing. We use a very aggressive regime of ACE inhibitors, Beta blockers, auto serotonin antagonists and ARBs. And that was also an unusual thing. We use the fact that they're supported with the pump to use both an ACE and an ARB together, but the idea that they have better blood flow in the cranial is way more tolerant and we give very high doses. So we use Lisinopril with the target dose of 40 milligrams, Coreg with a target dose of 50 BID, Aldactone 25 milligrams daily. Dr. Emma Birks: And then we add in losartan if they tolerate it and actually aim for 150 milligrams daily, so those doses are very high. And I think not normally given to people on LVADs. So you must've had the LVAD that don't tolerate the medical therapy and stop it. They might just have blood pressure control, etc. There is now also another INTERMACS trial, a sort of big study that's come out that actually shows benefit of neurohormonal antagonists in general. So that goes together with our study to show that they should already be given and then the regular testing. So we had quite thorough testing. So first of all, we do echos on the pump and then we do echos with the LVAD turned down to a speed at which is not contributing. So we do that and we do an echo at five minutes with it down 15 minutes, and then we walk the patient, distress them. Once we show that the hearts come down in size and improved function, then we do an exercise test, right heart cath on an off pump to look at the hemodynamics. Dr. Carolyn Lam: Wow. So tremendous effort and really the protocol is unique in and of itself, not just the pharmacological therapy, also the way this is monitored and decisions are made really, really amazing. Just one last question for me, because it's a humbling reminder of the importance of neurohormonal blockade in these patients. Do you continue that after they're explanted? Dr. Emma Birks: Yes, we do. And we continue aggressively and that's slightly different as well in that normally you wouldn't give a patient a nascent an up of course, but given that they've already tolerated it on the pump in that same patient. So we restart the same drug regime afterwards, and we actually like to get them to quite along that dosage before we discharge them from the XPLAN, we don't want to do that slowly. We get them back on it quite quickly. And then we follow them very carefully because we don't really know the long-term durability. Dr. Carolyn Lam: Wow, thank you. Hesham. I would love your thoughts on this paper. I mean, it really, really is remarkable results. Dr. Hesham Sadek: Yeah. I mean, I was very happy that we received this paper to review, frankly I've been following that work for a long time since the first new England paper that came out and I'd like to congratulate you for an amazing work. I think this will change the field. First, how was this trial different from the first trial, other than the fact that it's multicenter, what would you say are the major changes that you made to the protocol and what you've learned since the first trial? Dr. Emma Birks: Yes, you're absolutely right. We did make some changes. So first of all, it was six sites instead of one site. I think it was very important to reproduce it in the US but we changed the protocol itself as well. The first trial had optimization of the LVAD speed, really just by echo looking at the reduction in the ventricle size. It had the aggressive medical regime was very similar except this time we increased the Losartan dose from 100 to 150 after the Hill's trial came out. The testing was very frequent in the original English Sheffield study, probably a little bit too frequent to be able to be adopted on a wide scale. So we tried to reduce it down a little bit. So we decrease the frequency of the low-speed echos. I think we had them at six weeks, four months, six months, nine months in a year. Dr. Emma Birks: And after that, we saw if they were already improving and started and only did them at a year to 18 months, if they were improving. And then we also cut down the number of exercise tests. So we didn't do the exercise test until the echo was already showing significant improvement. For two reasons, one, we didn't find it very reliable and two, it was just too much testing for the patient. So it was more of a confirmatory test. In fact, it wasn't a requisite for a pump explantation. We didn't do a left heart catheter, which we did before. Previously we tried to measure LVEDP, this time we decided which was enough. So we just did a right heart cath on and off pump. And we did that once the echo was improved as well. So we rationalized that a little bit. And then the other important thing was before in hayfield study, once we saw the ventricular size come down and injection fraction start to improve, we actually added in Clenbuterol, which was a Beta-2 agonist. Dr. Emma Birks: And the idea with that was to cause a kind of physiological hypertrophy so that when you took the pump out, the heart didn't just dilate. We were worried about atrophy at the heart on the pump long-term. So we did that to try and improve the durability of recovery. So the reason we left off this time was really the previous protocol was very good, but was very complicated. So we wanted to see what rate of recovery we could get just with the aggressive reverse remodeling, neurohormonal drugs, plus the aggressive testing and the optimum loading with the idea that later on, we could add on either Clenbuterol or something later to improve the durability of recovery, if the ability of recovery is not good enough, but actually so far it's proven to be pretty good because the study itself takes quite a long time. It was sort of to recruit them. We had an 18 month period than the follow-ups. It was already a multi-year study. So we wanted to establish a regime that many centers could use to try and promote recovery. Dr. Hesham Sadek: I want to follow up on that last point, because as you know, I've looked at some of these Heights as well in our center, and we looked at the results with you and Stavros and others. So the myocytes size is expected to change, decrease with unloading, right with sufficient unloading. So how would you prepare the Myocardium to take on the normal afterload if you are not going to induce by a beta agonist, for example, Dr. Emma Birks: What I would like to do in the future is try using the pump itself actually. Sometimes there's heart recovers, the heart shrinks and actually start opening their own valve and working in the heart. Of course, when you have the HeartMate one, actually, sometimes wasn't synchronous with the heart. So sometimes the heart will beat against the pump anyway. Once you go to the continuous flow pumps, you've got continuous unloading. So I think it'd be very interesting to intermittently turn down the pump speed and load the heart to work it before you take the pump out. So I would really like to do that. I think that might be the next interesting phase of the study to improve your ability to.. So I guess once you've got maximum reverse remodeling and improvement in function, you could just turn the pump speed down to let the valve open. Dr. Hesham Sadek: Do you think perhaps if you do that, you will increase the percentage of patients that can be explanted? Do you think that could be a factor in the percentage of patient that can be explained? Dr. Emma Birks: I think it might be, it might more improve the, to your ability to make sure we have for a long, good echo function afterwards. Dr. Hesham Sadek: That's great. So another question this was limited to not ischemic cardiomyopathy patients. Can you elaborate a bit on why not include, for example, revascularized ischemic cardiomyopathy patients. Dr. Emma Birks: Yeah, so we did that really just because we didn't want to change too much from the original protocol. We also stuck with one device because we thought if you have multiple pumps, multiple diagnosis, it does get hard to analyze in a multicenter trial. So we did that on purpose and we were always trying to simulate the bridge to transplant population in the age group too. But actually interestingly, most of the patients recruited in the trial were destination therapy patients in the end. Dr. Emma Birks: I think this could be done with ischemic cardiomyopathy. I think we don't have enough data on ischemic cardiomyopathy to know whether it does or it doesn't recover. So I don't think our results say that it's only known as ischemics. I think it just means we haven't studied ischemics sufficiently. Logically they might have more scarred. It might be harder to get such a good percentage to recover. I think all of us in our individual centers have seen a few and we've sort of seen the on pump echo improved, and we've tested them and then taken some out. But most of these cases are anecdotal. So I think that is another important study that needs to be done, obviously a large group of patients. Dr. Hesham Sadek: I agree. So given that they're not ischemic cardiomyopathy, do you know how many of them had genetic testing or what is the percentage of monogenic cardiomyopathys or how do you think these patients would respond to this protocol? Dr. Emma Birks: But if you had a familiar history and actually found it didn't make any difference, whether they recovered or not. I think some of us have personally seen actually those were the familial cardiomyopathy tend to recover more actually again, anecdotally. We published a people before looking at the Titin gene saying that that did recover. I think actually only five of these patients, 12% of them had a family history, but some of them recovered Dr. Hesham Sadek: One final question, as you know, I'm a basic scientist. So ultimately the question I'm going to ask, what do you think the mechanism is? Is it that these hearts are just in a vicious cycle of remodeling and validation, increased pressure, and you were sort of giving it a chance for actual structural reverse remodeling where you changed the geometry of the myocardium and perhaps rest of myocardium, allow for improvement of calcium cycling dynamics, or do you think, is something more exciting? Like three-generation for example. Dr. Emma Birks: Yeah, that's very interesting because I think the LVAD doesn't unload, so it shrinks the ventricles. I think it does improve the geometry and the dynamics. And then you use the drugs where they may have felt before you almost put them from class four, heart failure into class three with the bad to give that chance to work again. And then I think various cellular and fibrotic factors have been looked at and it's hard because there was so many factors have been looked at that. You were going to find some that go up and some that go down and what's important. But the impression I get overall is that you do get improvement, the matrix limits, the recovery on the fibrosis and the matrix. Whereas you do get improvements of myocardial function and cellular function. The cells will tend to reverse the dysfunction and it's really whether that happens or not. It's probably limited a lot by the matrix Dr. Carolyn Lam: That is amazing here. Hesham, I'm going to put you on the spot. Do you have your own hypothesis about this Dr. Hesham Sadek: Based on the work that they did initially in the new England paper, we did actually a small pathology study looking at cell cycle of cardiomyocytes from the core samples and from the explanted hearts post-transplant and we saw evidence of increased cardiomyocytes cell cycle in these patients along with decreased DNA damage and some metabolic remodeling as well with mitochondria. So, you can't really tell much from tissue whether you regenerated it or not, but as you know myocytes don't divide and this is the basis for the lack of spontaneous regeneration of the myocardium. So if this in fact removes the block to cardiomyocyte cell cycle, then this might be a regenerative therapy mechanism. Dr. Carolyn Lam: Well, this is amazing. I wish we had all day to discuss this more. I mean, this is the only place you can get a discussion that goes from clinical to basic signs and back to clinical. Thank you so much, Emma and Hesham for sharing today. Thank you audience for joining us today. You've been listening to circulation on the run on behalf of Greg as well. Don't forget to tune in again next week. Speaker 1: Program is copyright the American heart association, 2020.
Julie answers 5 questions Lisa posted regarding experiences in recovery - reflect on them yourself and see what comes!
HeartMate III LVAD
This week we delve into the world of heart failure and transplantation and review a recent report from the ACTION Network about the use of the Heartmate 3 VAD for young patients. Does this device offer advantages over prior durable VAD's? What are the patient size limitations for such a device? Why might this device have fewer complications than prior devices? Dr. Matthew O'Connor, Assistant Professor of Pediatrics at The University of Pennsylvania shares his deep insights with us this week. doi: 10.1016/j.healun.2020.02.007.
This week we delve into the world of heart failure and transplantation and review a recent report from the ACTION Network about the use of the Heartmate 3 VAD for young patients. Does this device offer advantages over prior durable VAD's? What are the patient size limitations for such a device? Why might this device have fewer complications than prior devices? Dr. Matthew O'Connor, Assistant Professor of Pediatrics at The University of Pennsylvania shares his deep insights with us this week. doi: 10.1016/j.healun.2020.02.007.
As we have seen, woundmates are a doozy. They hook us in all sorts of unrelenting ways right on down to the end. The back and forth. The on again off again. The hot breakup sex. The unclear boundaries. The deep desire to keep the energetic "hit" going even as the relationship crumbles. Yup. Thats a woundmate breakup. In this episode we explore: • Why woundmates are so hard to break up with• Why woundmate breakups are highly dysfunctional, volatile and do a number on your system• What is actually behind the intense impulse to stay friends with an ex• What conditions make it appropriate to stay friends with an ex• How heartmate breakups look and feel and the process they willingly walk when it comes to healing and resetting• If you're going to be legit friends with a ex, an effective breakup-friends protocol to follow• If you're going through a woundmate breakup, the protocol to assist your healing and move you towards heartmate territory in the future. Are you in our Legendary Love Club?!? It's the after show hangout for all ya'll to meet, connect, jam about the episodes, get access to our movie club (think movies meets relational education training...ya it's a super funzie mashup, and it's FREE). The more the merrier!! To get into the group you have to answer the 2 questions (don't worry we don't share these) as a way to make sure all the peeps in the love club are there for similar and aligned reasons. Get into the FREE Love Club HERE
In this episode we dive more deeply into the complex nature of woundmating and trauma bonding. It can be scary to think we're stuck as a woundmate once we've had one or two woundmatey experiences. But good news, it's not a fixed identity, and the degree of woundmating or heartmating that comes through a unique relational pairing has loads to do with how two people's energies, stories, histories and personalities jive. ***In this episode we cover: • Why the labels of woundmate and heartmate are actually more fluid than you may think.• Having woundmate relationships doesn't doom you for your relational future and some proactive aspects to have on your radar to heal and integrate from these woundmate dynamics• Common characteristics that make woundmating appealing to have on your radar. • When we heartmate- what that looks like and common characteristics to have on your radar. • Our "Anti-Woundmate Diet" + Heartmate Manifesto***Mentioned in this episode: To download the FREE Anti-Woundmate Diet + Heartmate Manifesto click HEREIf you're not already over kicking it with us and all the other amazing love legends in our Podcast After Show Party Facebook Group, come join us!Every week we do a movie club which includes a LIVE session with Kelsey, plus other relational and podcast discussions!When you request access you'll be prompted with two questions to answer. We only accept requests from those who have answered them. These answers aren't shared anywhere in the group, but act as the door person to ensure the community remains energetically aligned, clear and a safe relational space for all the best kinda weirdo's ;)Get in on it HERE
Processing, processing, processing. If we're always processing, when are we actually living? Actually experiencing? Actually ENJOYING our relationship? Yup you guessed it. We're not. But that can change, first we must create more awareness around what is really going on, and we're here to help you do that this week! ***In this episode we cover: • When woundmates are actually aligned what that looks like.• How excess processing can be a bypass to true intimacy and being an active participant in our own lives. • Why conscious couples get all high and mighty about their non-stop processing parties, and what that actually *might* mean about the reality of the connection. • What to do if you and your partner are looping in processing processes and how to move towards repair more effectively. • The link between non-stop processors and woundmates• The link between conflict repair and heartmates• The difference between how woundmates and heartmates approach vulnerability, trauma and triggers.Mentioned in this episode:Ready to join our aftershow club? Next movie club session is Tuesday! Hop in there to be part of the magic!Get in on all the goodness HERE!
ACCEL Lite: Featured ACCEL Interviews on Exciting CV Research
In this interview, Michelle O'Donoghue and Mandeep Mehra discuss the final analysis of the 1,028 patient cohort outcomes of MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3).
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts, I'm Dr Carolyn Lam, associate editor from National Heart Center and Duke National University of Singapore Dr Gregory Hundley: And I'm Greg Hundley, associate editor from the Pauley Heart Center in Richmond, Virginia at VCU Health. Our feature article today really invokes thought regarding LVAD bridging to heart transplantation. I really look forward to the conversation with Dr Veli Topkara from Columbia University, the corresponding author and our associate editor, Dr Mark Drazner from UT Southwestern. And it's regarding the outcomes from their study, evaluating patients waiting for transplant that are bridged with an LVAD versus not. But before we get to that, let's dive into some of our other original articles with our little coffee chat. Do you have an article that you'd like to discuss? Dr Carolyn Lam: You bet I do Greg and I have my coffee here. Have you ever wondered, does microvascular disease, in any location in the body, increase the risk of lower limb amputation? Well, this was looked at in the paper that I chose first today. It's from Dr Beckman from Vanderbilt University Medical Center in Tennessee and his colleagues, and they basically examined 125,674 participants in the Veterans Aging Cohort Study from 2003 to 2014 and analyzed the effect of prevalent microvascular disease defined as retinopathy, neuropathy and nephropathy and peripheral artery disease status on the risk of incident amputation events, of which there were 1,185 amputations over a median of 9.3 years. Dr Gregory Hundley: Wow, Carolyn. What did this study find? What did Josh and his colleagues find? Dr Carolyn Lam: They found that the presence of microvascular disease increases the risk of amputation significantly in the absence of peripheral artery disease. As many as one in six below knee amputations may result from microvascular disease, even without peripheral artery disease. Microvascular disease also potentiates the amputation risk in persons with peripheral artery disease to more than 20-fold, compared to persons with neither peripheral artery disease nor microvascular disease. Further research is really needed to understand the mechanisms by which this occurs. And in the meantime, clinicians should bear this increased risk in mind when screening for and managing lower extremity disease. Dr Gregory Hundley: Ah. Well Carolyn, my first paper is somewhat related because we're going to talk about triglycerides. And this paper is from Zahid Ahmad from UT Southwestern Medical Center. He's the corresponding author. And can you imagine Carolyn an antibody that could correct elevations in serum triglycerides? Dr Carolyn Lam: Tell us about it, Greg. Dr Gregory Hundley: Well, I'm going to give you a little background first. Low levels of triglycerides and other lipids are observed in individuals with loss of function mutations in angiopoietin-like protein 3 which inhibits lipoprotein lipase activity, increasing triglycerides and other lipids, and providing a rationale for development of a monoclonal antibody therapy. Dr Carolyn Lam: Interesting. What did this study do Greg? Dr Gregory Hundley: It evaluated evinacumab. They looked at the safety of this. This is a fully human angiopoietin-like protein 3 antibody, and it was compared with placebo, with no serious treatment emergent adverse events, no events related to death or treatment discontinuation was reported. They did two phase one studies evaluating single and multiple ascending doses. In addition, substantial and sustained percent reductions from baseline versus placebo were observed and triglycerides with absolute levels reaching about 50 milligrams per deciliter for several of the evinacumab doses at specific time points in both studies. And therefore, the data from these two phase one studies in this one paper support further clinical evaluation of this new antibody in larger studies of hypertriglyceridemic individuals. Dr Carolyn Lam: Definitely a space to look out for. Well Greg, my next paper is a basic paper. Genome wide association studies have identified chromosome 14 Q32 as a locus for coronary artery disease. The disease associated variants fall in a hitherto uncharacterized gene called Hedgehog Interacting Protein Like 1, or HHIPL1. the function of this gene and its role in atherosclerosis has previously been unknown, well, until today's paper. But Greg, here's your quiz. What do you know about the hedgehog proteins? Dr Gregory Hundley: Well, I know hedgehogs are friendly little animals and I know they must have great proteins because they're so friendly. Dr Carolyn Lam: Why did I expect that? Oh, let me tell you a little bit about them. The mammalian hedgehog proteins like sonic hedgehog, desert hedgehog, and Indian hedgehog are secreted molecules that exert a concentration and time dependent effect on target cells following binding and complex signal transduction pathways. They induce the transcription of target genes, primarily involved in cell proliferation, survival, and fate specification. Now in adults, the hedgehog signaling is involved in the maintenance of adult vasculature and ischemia induced neovascularization, including after myocardial infarction. Today's authors, however, including Tom Webb from University of Leicester and colleagues, report the first experimental investigation of HHIPL1 and the present evidence that it is a secreted proatherogenic protein that regulates smooth muscle cell proliferation and migration. So, that's novel. Through a series of experiments involving coronary artery disease, relevant human cells and mouse models, they showed that HHIPL1 is a secreted protein that interacts with sonic hedgehog and is a positive regulator of hedgehog signaling. In murine models, HHIPL1 deficiency attenuates the development of atherosclerosis by reducing smooth muscle cell proliferation and migration. The clinical implications are two-fold. First, this study supports HHIPL1 as the causal gene at that 14 Q32 coronary artery disease locus that we did not really understand previously. And secondly, HHIPL1 is a promising therapeutic target that affects a pathogenic mechanism not addressed by current mechanisms for coronary artery disease. Room for novel development. Dr Gregory Hundley: Very interesting Carolyn. Well, I've got another basic science paper, and this is from Dr Kenneth Walsh at University of Virginia and it's going to look at the role of neutrophils, not necessarily macrophages but neutrophils and their role in pressure overload induced cardiac dysfunction. While the complex roles of macrophages in myocardial injury is widely appreciated, the function of neutrophils in nonischemic cardiac pathology has received relatively little attention. This study examined the regulation and function of neutrophils in pressure overload induced cardiac hypertrophy as mice underwent treatment with Ly6G antibody to deplete neutrophils and then subjected them to transverse aortic constriction or TAC. Dr Carolyn Lam: Huh? What did they find? Dr Gregory Hundley Caroline, the study revealed that neutrophils played a critical role in the hypertrophy of the left ventricle that results from pressure overload in this murine model of heart failure and identified that a non-canonical Wnt protein is essential for the recruitment of neutrophils to the injured myocardium. Dr Carolyn Lam: Hmm. What do you think are the clinical implications of this? Dr Gregory Hundley This study demonstrates how neutrophils contribute to the hypertrophy of the left ventricle under conditions that do not involve ischemia or myocardial necrosis. Also, since cardiac hypertrophy is a risk factor for the development of heart failure, this study implicates WnT5a mediated neutrophil infiltration as an early step in the progression of this disease. Dr Carolyn Lam: Wow, thanks Greg. That was so cool. But let's hurry on to our feature discussion, shall we? Dr Gregory Hundley You Bet. Dr Carolyn Lam: Bridge to transplant with left ventricular assist devices is a mainstay of therapy for heart failure in patients awaiting heart transplantation. The criteria for heart transplantation listing does not differ between patients medically managed versus mechanically bridged to heart transplant. However, are there differences in post-transplant outcomes between medically managed and mechanically bridged patients? Well, today's paper provides important data to address this question. So pleased to have with us the corresponding author, Dr Veli Topkara from Columbia University Medical Center, New York Presbyterian as well as Dr Mark Drazner, associate editor from UT Southwestern. Welcome gentleman. Veli, this is an important question. Could you please tell us how you addressed it and what you found? Dr Veli Topkara: We decided to visit an old question of whether bridging with LVAD confers at risk for post-transplant mortality. Because the field and pump technology has been rapidly changing. There has been a significant increase in utilization of devices nationwide to the extent that more than 50% of patients already have an LVAD in place by the time they receive a heart transplant. And patients also wait much longer on these pumps before they could get a heart. Currently, available devices provide continuous flow and patients essentially live without a pulse for many months to years waiting for a heart. And with this unique physiology, they also have unique complications such as RV failure and there has also been pre-survey reports including one from our center suggesting an increase in the primary graft failure rates after heart transplant. And mostly seen in patients who were bridge to transplant with an LVAD. To address some of these questions, we took advantage of the UNOS database, which is the largest prospective transplant data registry in the United States. We were able to identify more than 14,000 patients who are either medically or mechanically bridged to transplant. We then derived a cohort from patients who were LVAD baseline by propensity score and we looked at their outcomes. And what we found was that patients who were mechanically bridged to transplant with an LVAD, had 9.5% mortality at one year, compared to 7.2% in patients who were medically bridged. And this is more than 30% increase in relative risk of death for LVAD patients. When we looked at the specific cause of death at one year, LVAD patients had a higher number of cardiovascular death secondary to primary graft failure, confirming findings of the recent studies at a larger scale. Next, we looked at whether mortality risk factors were similar in the mechanical versus medical bridged patients. And this is a very important question clinically because the criteria for transplant listing do not distinguish between the two patient cohorts. For example, at my center age cutoff transplant listing is less than 72 years of age and that is whether or not patients are on VAD support. And same applies for example, GFR cutoff for renal function or PVR cutoff for pulmonary hypertension. And all the cutoffs that are utilized are essentially identical for transplant candidates irrespective of the bridging strategy. But what we found in this paper, however, what's quite different that if we apply the same thresholds for mechanical versus medical bridged patients, for some of these risk factors, you end up having outcomes that are remarkably different. For example, for patients with a normal renal function, the mortality risk is similar going into transplant with or without an LVAD, but for patients with borderline renal function observed mortality has more than doubled for those going into transplant with an LVAD, as opposed to medical therapy. And we also observed similar trends for recipient age, BMI and PVR, in which numerical increase in these factors would translate to high risk of mortality in LVAD patients going into heart transplant. Despite the limitations of this large registry analysis, I think these findings suggest that we may need to think of it differently when it comes to listing or transplanting patients who are on LVAD. And there seems to be a group of patients who are perhaps maybe better served by staying on an LVAD as opposed to moving on to heart transplant and we need to better identify who these patients are. Dr Carolyn Lam: Oh Wow. Veli, thank you. First, congratulations on a very important paper and also how you beautifully summarized. Mechanically bridging patients associated with a higher risk of early post-transplant mortality and even providing data on the cause and risk factors associated with that mortality. Mark, could I bring you in here? Not just as AE (associate editor), but as a doc[tor] who manages many of these patients. What were your perspectives? Dr Mark Drazner: As I step back and as Veli said, there's an increasing number of patients who are being bridged with a VAD, so the question clearly is important, and we don't really have any randomized data available to us in terms of how the bridging strategy may impact outcomes. When you look at the groups of patients who are supported with VADs or not, they're very different and so you need to do some statistical manipulation which here they did propensity matching, to try to come up with equal groups as you look at their outcomes. That was nicely done. And then theoretically I think you could argue there may be reasons why patients bridged with VADs may do better or they may do worse. They may do better because you may restore their functionality, you may improve renal function and, but they may do worse because they have coagulopathies, the VAD itself may lead to complications and so it's a question you can't really answer just logically. You really need some data which is I think the best study that's been brought forward so far as the one we're discussing today. Veli, let me ask you because the obvious question then is why do you think the outcomes are worse among the patients who are bridged? Dr Veli Topkara: I think they are doing worse for multiple different reasons. Having an LVAD is clearly an additional surgery which technically makes the second transplant surgery more complicated. But when we looked at the risk factors for primary graft failure at our institutions, the predictors of primary graft failure in LVAD patients were also very similar to factors we identified in this nationwide analysis which included renal failure, RV dysfunction, as well as trans-transplant and increased time on device support. I think it's clear that some subset of LVAD patients who have these risk factors are at higher risk for increased post-transplant mortality for some of the mechanistic reasons are unclear at this point. Dr Mark Drazner: Do you think their continuous flow exposure is part of it? Dr Veli Topkara: That's clearly one of the hypotheses that we have been talking about because as we discussed, these patients are exposed to continuous flow for a long time and one of the concerns is whether they lose their peripheral arterial venous-reactivity over time. And this could potentially also be the reason why patients who are on pump support for longer times are at higher risk for PGF. That's a possible underlying mechanism. But in this data set, we didn't have fair data with regards to pulse pressure and pulsatility, which could have helped answering this question. Dr Mark Drazner: And just for clarification for the listeners, this was pre-HeartMate 3 data, is that correct? Dr Veli Topkara: Yes. This analysis doesn't include any HeartMate 3 patients. Dr Carolyn Lam: And Mark, if you don't mind, could you also clarify for the listeners why you specifically pointed out HeartMate 3 in the setting of the pulsatility? Dr Mark Drazner: There is some degree of pulsatility reintroduced with the HeartMate 3, whether that has any physiological consequences is not yet known. Certainly, in terms of the impact of transplants. But as Veli said, the dataset available didn't yet include the HeartMate 3 so that's, remains an unanswered question for us currently, but certainly an important one. Dr Veli Topkara: We would probably be able to do this analysis now that we have accumulated more patients with HeartMate 3. At the time of the study we didn't have any HeartMate 3 patients in the registry. In terms of primary graft failure, we have implanted over 160 patients with HeartMate 3 at my center, but we still see primary graft failure in HeartMate 3 patients going into heart transplant, but that would clearly be an interesting follow up project. Dr Mark Drazner: Yeah, for sure. Another point that people, as they looked at your paper and asked me, is in terms of the impact of the VAD complications, whether the patients who are doing worse or those who, because they are patients who had VAD who have had complications and then went on a transplant and the impact of that, in terms of your findings. I know you did some analyses on that. Could you just clarify that for our listeners as well? Dr Veli Topkara: Sure, so we wanted to look at for the LVAD patients, if there were any VAD related factors that would impact the posttransplant mortality and one of the things that we looked at was, their specific complications on LVAD support and were able to pull that data by looking at their reason for 1A upgrade status which clarifies the complication pipe. And when we looked at, based on complication type, we didn't see any impact of complication on the post LVAD mortality. In other words, the other patients who are transplanted with an infection or they were transplanted because of device thrombosis, they did not have any difference in terms of their posttransplant mortality. We also compared patients who were supported by axial flow devices versus centrifugal flow devices and again, there was no significant difference in terms of posttransplant mortality. One factor that we found that was significant was the duration of the LVAD support and patients who stayed on the LVAD for longer times clearly had increased higher risk of posttransplant mortality. And this is also something that we had found in our institutional data. Dr Mark Drazner: And Veli that would potentially speak to the impact of the continuous flow if duration of VAD is a risk factor. Dr Veli Topkara: That's our hypothesis Mark. And I think we all tend to think that continuous flow is not natural, and we have pulse style flow for a reason. Now it's possible that if our bodies and end organs and vessels are exposed to continuous flow for a long time, that may be potentially a reason for, increased risk of PGF or raise of PGF after heart transplant. But I don't think we have enough data yet. Dr Mark Drazner: Veli, one of the other interesting findings was the lack of impact on long-term outcomes. I'd be interested in your thoughts about that, why there was an impact on the first year but not long term. Dr Veli Topkara: Absolutely. And that was a critical part of the findings and when we looked at our survival, when we visually looked at the curve, it seemed like the curves really separated early on and they sort of remain parallel to each other after one year. And for that reason, we did a conditional survival analysis starting from one year and then we compared starting for one year. There was actually no difference between the LVAD versus medical group. Again, confirming that the adverse impact of survival was really early, within the first year after transplant and I think that really has to do with primary graft failure as well as vasoplegia which are, typically seen early posttransplant. And I think the reason the VAD support is increasing mortality is most likely through increasing risk of PGF as well as vasoplegia. Now that's my read on the early risk rather than the late impact. Dr Mark Drazner: Do you think that speaks to maybe not as big an impact on the immunological milieu of VADs as one might anticipate? Dr Veli Topkara: Certainly, I mean the immunology, one thing we know is that LVAD patients have higher HLA sensitization going into transplant. However, primary graft failure is typically very early after transplant. And in general, we don't find, obviously we don't see any rejection in these patients. The mechanism is not related to HLA mediated rejection. Dr Mark Drazner: That's interesting. Dr Carolyn Lam: Well Mark and Veli, thanks so much. This is such an important and interesting discussion. Could I wrap it up now by asking each of you, you've already covered possibly the important areas for future research including the pulsatile devices, but what should clinicians take home right now? Veli, if I could start with you, because you had already said earlier that perhaps these patients need to be more carefully considered. What do you mean by that? What's the take home for now? Dr Veli Topkara: I think the question is whether we should be listing or transplanting LVAD patients who are high-risk, and I think the research should focus on developing tools to better identify LVAD patients who are too high-risk for transplant. In this project, we only worked with a limited number of variables that were available in the UNOS registry, but there may be more specific clinical risk factors or even biomarkers predicting outcome in this unique cohort of LVAD patients potentially transitioning into transplant. I think that's an important question to figure out. And another important question is whether we should be using identical cutoffs for listing patients with or without LVAD and if not, what would be the ideal cutoff for each one of these risk factors? Because what I read from this paper is that, a creatinine level of 1.8 may signal a different risk in an LVAD patient versus another patient on a minor trump. That's another important question. And also, since October of last year, the new heart allocation policy has been in place, which now defines LVAD patients to appear status three or four based on their complication profile. And it will be interesting to see how the new allocation system would impact patients are on LVAD support waiting for an organ. And it's possible that these patients may end up waiting longer compared to patients who are with cardiogenic shock and are assigned to higher tier status. And if LVAD patients wait longer as we see from this data, they will have worse posttransplant outcomes. It's going to be very interesting to see how the new allocation policy impacts. Another point I want to make is that with the recent MOMENTUM-3 trial patients receiving HeartMate 3 LVADs, had a 13.4% mortality risk at one year and this is actually lower than 17.6% mortality at one year in high risk LVAD patients in our study. Again, questioning transitioning from LVAD to transplant in high risk patients. Dr Mark Drazner: I might take a step back even further. It's an important, it touches on a critical question in my mind, which is if you have a patient who needs to go into transplant and they're not crashing and burning. I'm assuming if they're crashing and burning, you need to go onto an LVAD, the following comments won't apply to that group. If you're a patient who's relatively stable, is it a better strategy to try and get them to transplant directly? Or is it better to go through and VAD and then transplant them? And ultimately that strategy question I think would require randomization to really answer that. But the data that we have discussed today, I think are opening that question and touch upon that in terms of the strategy of the impact of bridging people with VADs itself, which is why I think this is such an important question. Dr Carolyn Lam: Thanks again, Mark and Veli. That was an amazing discussion. Thank you, audience, for joining us. You've been listening to Circulation On The Run. Don't forget to tune in again next week. This program is copyright American Heart Association 2019.
Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Caroline Lam, associate editor from the National Heart Center and Duke National University of Singapore. Greg Hundley: And I'm Greg Hundley, Professor at the Pauley Heart Center of Virginia Commonwealth University Health Sciences in Richmond, Virginia. Dr Carolyn Lam: In case you guys missed us last week, this is how our new podcast is gonna work. Greg and I are going to invite you for coffee with us, almost with a journal in hand, and we're gonna chat about the week's issue, highlighting two original papers each, that we thought were awesome. And don't you worry, the feature discussion is still there, authors will join us for a feature discussion right after our coffee. And for this week, the feature paper speaks about the MOMENTUM 3 trial, and talks about the important analysis of stroke outcomes in this trial. But before that, I think Greg, you've got a couple of papers don't you? Greg Hundley: Absolutely Carolyn. So the whole issue, I think we're gonna pick out several stroke papers, really a stroke theme. The first paper is Ankit Maheshwari. He looked at the utility of P-wave morphology on the 12-lead electrocardiogram, to help predict ischemic stroke in patients with atrial fibrillation. Now, how did he do this? Basically, they looked at a large cohort of individuals from the ARIC study, and these were patients that developed atrial fibrillation. And electrocardiograms had been recorded prior to their Afib episode. So, what were they looking for in P-wave morphology? Well, they were looking for changes in Lead three. They were looking for changes in V1. They were also looking for extension of that P-wave. So a prolonged duration. And what they observed, is that that abnormal P-wave, could forecast abnormal atrial remodeling, that might be an indicator of future stroke. Dr Carolyn Lam: Huh, interesting. But is it really reproducible? Did they validate it somehow? Greg Hundley: Yeah, so that's great Carolyn. You know, in papers like this, you like to take a finding in one large cohort, but then you've got to reproduce it. So they went to the MESA Study. Remember now, Mesa are individuals without cardiovascular disease. ARIC are patients with cardiovascular disease. And the finding was reproducible in MESA. Also, what the authors did, is they looked at the relevance of this EKG finding to our existing CHADS-VASc2 scoring system. And what was really smart by these investigators, is that if you added the information from the abnormal P-wave morphology to the CHADS-VASc2 score, you could forecast stroke. Now you say, well CHADS-VASc2 is already pretty reliable, but what about those patients that have a CHADS-VASc score of one right? We're always kind of wondering, do we anticoagulate them? Do we give them aspirin, et cetera. Well if the P-wave morphology was abnormal and they were at higher risk for stroke, that could sway you as a clinician, to go ahead and prescribe anticoagulation for that group of patients. And something very simple, just from the 12-lead EKG before the patients went into atrial fibrillation. You've got a paper that also is sort of focusing on stroke. You want to tell us about that? Dr Carolyn Lam: Yeah, one big data to another big data series. This time, it's Get With The Guidelines Stroke series, and this paper is from Dr Menon from University of Calgary in Canada. Where they described the door to treatment times for endovascular therapy in acute stroke. What is that? Well that's a time interval from when the patient arrives in the emergency department or the door, to the first pass of the treatment initiation and endovascular therapy. And basically they found that the median door to first pass time was 130 minutes. Only 3% of patients achieved a door to first pass time of less than 60 minutes. In multivariable analyses, older age arrival during nonregular hours and a history of diabetes, were all associated with the longer door to first pass time. And finally, among hospitals with an annual endovascular therapy case volume of 40 or less, every five unit increase in that volume was associated with a 3% reduction in this door to first pass time. Greg Hundley: It sounds like that could be really useful information for stroke centers, you know, that are managing these patients acutely. How do you think these results are going to impact that Carolyn? Dr Carolyn Lam: Great question. So first thing is, I think it provides some benchmark times for this in hospital workflow, and it obviously shows areas of improvement. For example, improving workflow during nonregular hours, or increasing the experience of a center, and basically emphasizes the point that efforts on streamlining workflow and saving time, need to continue so that the full potential of endovascular therapy is realized. Greg Hundley: Oh wow, that's outstanding. I'm gonna transition sort of to a basic science paper, also trying to help manage patients with stroke. This one is looking at the safety of all of the dehydrogenased right stem cells. Well, what the world is that. In animals, what has been shown previously, is this particular cells type, that's harvested from your bone marrow, can be infused into the carotid artery, and those animals experience smaller neurologic deficits after stroke. And so with that encouraging result in animals, these investigators sought to test the efficacy of this type of therapy, well not really the efficacy, but the safety of this type of approach in those patients that have sustained actually quite a large stroke. You had to have a relatively large neurologic deficit to qualify for this study. And just quickly, the way this works is these cells enter up through the bloodstream and they modulate inflammation. By modulating inflammation, that facilitates healing in the stroke patient. Dr Carolyn Lam: Yeah, but wow. I mean bone marrow, biopsy and isolating the cells and so on. How is the study done? Greg Hundley: So, the key here is you've had your stroke, you're still in the hospital with a large neurologic deficit. And so day 11 to 17, you undergo a bone marrow biopsy. Then the cells are purified, and they're reinfused into your carotid artery by the way. And so, what was the study trying to do? Well, it was actually looking at the safety off all this. And what would the concern be? You're infusing these cells into the carotid artery. They go into the cerebral microcirculation, and those that are working in this field, are concerned is that going to promote more emboli? Is that going to promote thrombus? Extend the size of the infarct in the brain, et cetera? So, the investigators performed MRI's and neurologic exams. And what they found is the neurologic findings in the patients really didn't change, so there was no benefit. But the study wasn't set up to look for a benefit. And there were four patients that had a little bit of an enlargement of the stroke observed on MRI. So, a lot more to come in this basic science realm, but it's interesting to see investigators thinking about this in a whole different way, where we're harvesting one cell type from your body, and then infusing it up into the brain to sort of help rescue the situation. Dr Carolyn Lam: Well, another paper dealing with stroke. This time, a Mendelian randomization study to explore whether genetically determined circulating levels of cytokines and growth factors, may be associated with stroke. And this was done in the mega stroke GWA data set and validated in the UK biobank, and it’s by Dr Dichgans and colleagues from the university hospital, Ludwig Maximilian University of Munich. They basically found, that a genetic predisposition to higher circulating levels of monocyte chemoattractant protein one, was associated with a higher risk of stroke. The associations also found for the etiology of the stroke subtypes, and especially for large artery stroke and cardioembolic stroke. In fact the genetically determined levels of this monocyte chemoattractant protein one, was also associated with higher risk of the related phenotypes of coronary artery disease and myocardial infarction. Greg Hundley: So, how do you bring this to practice in the clinic Carolyn? Dr Carolyn Lam: So, this is still some steps away, but I do think that it very nicely supports the idea that inflammation as part of the pathogenesis of stroke, and of course additional work is needed to determine whether targeting the specific monocyte chemoattractant protein one, or it's downstream effectors, may be a meaningful strategy to lower stroke risk. So, terribly interesting. Greg Hundley: Yeah, you know it sounds like hitting inflammation or targeting that, is a real theme here from the basic science group. Well this is great Carolyn. And now, I guess we'll transition over to our feature article. Dr Carolyn Lam: Absolutely. So, we're here to discuss the long-term results of the MOMENTUM 3 Trial, and that was a randomized controlled trial of the HeartMate 3 versus the Heartmate II left ventricular assist device. And this time, with a focus on stroke. The outcomes that's just so important to our patients. Greg and I are incredibly pleased to have with us, the authors, Dr Mandeep Mehra from Brigham and Women's Hospital, as well as our senior associate editor, Dr Biykem Bozkurt, to discuss this paper. Mandeep, perhaps just set the scene by telling us what this secondary analysis found? Dr Mandeep Mehra: This analysis is really focused on the issue of stroke, as you pointed out. I'd like to just lace into context what this is important. Ever since the advent of left ventricular assist device therapy from the 80s and early 90s, to now, one of the major Achilles' heels, whether we have used pulsatile flow devices or non-pulsatile flow devices, has been the very constant occurrence of a high incidence of stroke, beyond the stroke rates were predominantly as compared to ischemic strokes. Then with the newer devices, we actually saw a reversal, where we began to see more ischemic strokes as opposed to hemorrhagic strokes, almost an equal parts at this time point. And this has been one of the critical reasons why we have not been able to expand the therapy beyond the very, very sick patient. Greg Hundley: Very nice. And another particular in the results here is, you didn't really see a difference in stroke rates, either hemorrhagic or ischemic strokes early, but you did start to see a difference after 180 days. Why do you think that's the case? Dr Mandeep Mehra: That's a great point Greg. We really saw no difference in the first 30 days. When we analyzed this data, we divided it into a perioperative, a first 30-day time point. Then, we looked at the short-term time point up to 180 days or six months, and then beyond that to the two year end point. What became very clear is that most of the gains that we saw in the stroke rate, began to appear after the first 30 days, did not quite reach statistical significance at six months, but really the differences became heavily pronounced after six months, all the way out to two years. So, first point that I would make Greg, is that we did see differences beyond 30 days, it's just that they didn't reach conventional statistical significance. The second thing is, the more important point that you make, asking why that was the case. We actually think that the reason behind that, is that the first three months or so after that implant, really is a period of chaos in these patients, where the hemocompatibility, which is essentially the interface between the device as well as the patient, is attempting to be established. And it's very similar in a way as we see in heart transplantation Greg, where the real challenge in heart transplantation is between rejection and infection. And in the case of left ventricular assist device is the challenges between bleeding and thrombosis. It turns out that three months, whether it be transplantation or whether it be left ventricular assist devices, seems to be this period of chaos and adjustment, during which the patient and the device are starting to get to know each other. And this is why we think that most of the gains occurred after this period of chaos was overcome. Greg Hundley: No, it's really interesting that after accounting or adjusting for all the anticoagulant drugs, antiplatelet drugs, even the other medical therapies that were applied, you found these results. I mean, maybe also bring in Biykem here to answer the question, what is this machine doing that's providing such a benefit? Dr Biykem Bozkurt: The two-year results being quite impressive for the HeartMate 3 are truly encouraging. Because I think we truly see a concordance benefit beyond 180 days, especially the nondisabling strokes, giving the hope to the providers that we can further perhaps enhance the field by focusing on optimization of anticoagulation strategies, prevention of atrial fibrillation, and maybe even consider our algorithms or pathways for stroke. Because, in this protocol, even though the stroke management was not standardized, and I'm sure that the data will not yield that information as to which centers were able to approach the stroke management in a perhaps evidence based approach, the sobering facts are regardless of the device, at two years, approximately half of the patients died. Even the non-disabling stroke patients had increased mortality compared to no-stroke patients. And if you examine evidence-based approaches, only one-third of the hemorrhagic stroke patients had reversal of anticoagulation, and a very small percentage ... actually, none of the patients had device intervention for the ischemic stroke. That raises the question of yes at two years the HeartMate 3 results are very promising. But, can we further even advance the field by doing evidence based standardized pathway driven stroke treatment approaches. The other very interesting finding from this trial is, in ENDURANCE trial, which was another trial with centrifugal device, HVAD device, there was an association of the stroke rates with inadequate control of blood pressure and anticoagulation, which was not noted in this trial. Maybe Mandeep can comment on do we truly have the adequate power to be able to infer whether blood pressure control and/or appropriate anticoagulation management strategies will matter? Dr Mandeep Mehra: Biykem you've said it really well, and I'd like to just make some additional points with respect to the question. So, first of all Greg you're absolutely correct, that we tried to search for anything that would predict this reduction in stroke with the HeartMate 3, and it turned out that all we were left with is the device itself. So, it really begs the question, what is it about the device or it's interface that may have resulted in this. And of course, some of what I'm about to tell you will be speculation, but it may actually carry some water. So, for example, the HeartMate 3 is very unique in one other aspect, and that is that, even though it's a small profile device, it's engineering principles are such that it allows for very wide blood flow pathways. And in fact, despite its small profile, the blood flow pathways allow for 20 times more red blood cells to travel through the primary and secondary pathway, than other devices. What it means is that as blood is going through this device, it is exposed to very low sheer stress. And in return, the benefit that we see very clearly with this device in a very, very important way, is the fact that we see almost no denovo pump thrombosis developing with this device. Certainly, if the device doesn't carry some small quad risks in it, that cause problems with the device, it's probably also not causing the production of smaller non-device malfunction producing thrombi, which may with other devices, actually develop and cause strokes. So, we think that particular engineering enhancement, may play a very important role in reducing this stroke rate that we have observed. The second very important point that Biykem brought up, is this notion about the management of ... whether it be with anticoagulants or with blood pressure management. And for a moment let's dwell on the blood pressure issue. One of the striking things with the other centrifugal device, the HVAD device, is that the ENDURANCE Trial showed a significantly higher stroke rate with that device. And in fact, in a subsequent study, the ENDURANCE Supplemental Trial, when blood pressure was tightly, tightly controlled in the device, there appeared to be a small signal in reduction in strokes, although it still did not meet the non-inferiority endpoint, compared to the HeartMate II in the second supplementary trial that was done with that device. So, what's unique about this? Well, we can very clearly say maybe we just didn't have enough ability to show a difference in this particular trial, we didn't analyze it the right way, because we didn't have a blood pressure intervention or low or higher permissive blood pressures in this trial. But I would say that there's one other issue that I think may have played a very important role in this, and that is the HeartMate 3 is intrinsically developed with a fixed pulse algorithm. And in fact, the HeartMate 3 has a capacity where the magnetically levitated rotor upregulates itself and then downregulates itself every two seconds, and creates an internal pulsatility. Now, engineers developed that pulsatility to really decrease stasis, so that the pump wouldn't thrombose. But we often see that it provides sufficient peripheral pulsatility, not to the pulse pressures that we would normally like to see, but certainly to some degree, where the vasculature can perceive or transduce some degree of pulsatility. Why that may be important is, that it may actually allow for preservation of baroreceptor function in these patients, which tends to be lost in continuous flow pumps. And how important that is for blood pressure regulation and its vascular effect, may be something that needs to be looked at into the future. But it's certainly a very, very intriguing issue for us to examine. Dr Biykem Bozkurt: Mandeep, one final question or comment. Do want to comment on the stroke rates of HeartMate II compared to former trials. Because that comes as a common query as to why in MOMENTUM 3 the stroke rate in HeartMate II, appear to be higher than the former trials. Dr Mandeep Mehra: So very quickly, I'll tell you they're not. So, if you look at the 2009 randomized trials, randomized patients with a HeartMate II versus the HeartMate XVE trial, the two-year stroke rates with the HeartMate II in that trial were 19%, exactly what we observed at two years in this trial. Other trials have shown exactly that same number. The only trial in which there appeared to be a difference in those numbers, was in the ENDURANCE Trial, where the two-year rate of any stroke was 12%, and was a little lower in the HeartMate II than what we observed. However, I will caution you that if someone dies before having a stroke, then they die without a stroke. And so, stroke can sometimes we underestimated if the population that is enrolled, such as a transplant ineligible population at very high risk, is dying more often than having the chance of a stroke. So, I actually do not think at all that there was any difference whatsoever compared to prior trials. And even when you look at the ENDURANCE Supplement Trial, which is probably the most contemporary comparison of HeartMate II stroke rates, with MOMENTUM 3, the ENDURANCE Supplement Trial was only a one year trial, and the stroke rates even at one year were right on target with what we observed at the HeartMate II group in MOMENTUM 3. So, frankly that criticism is probably an unfounded criticism. Dr Biykem Bozkurt: Thank you. Dr Carolyn Lam: Wow, thank you Mandeep and Biykem, for really helping us go under the hood with this paper. I'm heart failure trained as well, but I learned so much, I'm sure our listeners did as well, and I'm sure you agree too Greg. Thank you so much for joining us today. Don't forget to tune in again next week. This program is Copyright American Heart Association 2019.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. This week's issue provides much long awaited healthcare resource utilization and cost implications in the MOMENTUM 3 randomized controlled trial of a magnetically levitated cardiac pump in advanced heart failure. All of this coming right up after these summaries. The first original paper this week provides important mammalian data on the acute effects of phosphodiesterase type 1 inhibition on the heart. Now phosphodiesterase type 1, or PDE1, is known to hydrolyze cyclic AMP and cyclic GMP in the heart. However, what's important to understand is that data from rodents may not be applicable to humans because rodents express mostly the cyclic GMP favoring PDE1A isoform, whereas human hearts predominantly express PDE1C isoform which has a balanced selectivity for cyclic AMP and cyclic GMP. In today's paper, first author Dr Hashimoto, corresponding author Dr Kass from Johns Hopkins University School of Medicine and colleagues, determined the acute effects of PDE1 inhibition on PDE1C expressing mammals, dogs and rabbits, in normal and failing hearts. They found that selective inhibition of PDE1 with ITI-214 induced positive inotropic, lusitropic, chronotropic, and arterial vasodilatory effects in dogs and rabbits. These effects occurred via cyclic AMP modulation and were observed in failing hearts. ITI-214 contractile increase was insensitive to beta adrenergic blockade or heart rate increase, but inhibited in vivo by adenosine receptor inhibition. Furthermore, isolated myocytes revealed differences between PDE1 and PDE3 inhibition. Wherein PDE3 inhibition, augmented beta receptor agonism and calcium transients, whereas PDE1 inhibition enhanced function without calcium increase. These findings have important clinical implications for ITI-214 which has completed phase 1 trials and may provide a novel therapy for heart failure. We know that macrophages are involved in foam cell formation in atherosclerotic plaques, but our next paper tells us we may now have a way to therapeutically modify this. Co-corresponding authors Dr Wei and Schober from Ludwig Maximilian's University Munich elucidated the role of microRNA generating enzyme Dicer in macrophage activation during atherosclerosis. They showed that Dicer deletion in macrophages accelerated atherosclerosis in mice, along with enhanced inflammatory response and increased lipid accumulation in lesional macrophages. In vitro, alternative activation was limited, whereas lipid filled foam cell formation was exacerbated in Dicer deficient macrophages due to impaired mitochondrial fatty acid oxidative metabolism. MicroRNA biogenesis promoted the degradation of fatty acids by mitochondrial respiration in macrophages, which in turn reduced intracellular lipid storage and limited atherosclerosis. Thus, reducing foam cell formation in atherosclerotic arteries by enhancing energy metabolism through microRNA mediated fatty acid oxidation may be a promising approach for the treatment of atherosclerosis. The next study evaluates how aortic stiffening relates to resting cerebral blood flow and cerebral vascular reactivity in older adults. First and corresponding author Dr Jefferson from Vanderbilt Memory and Alzheimer's Center and her colleagues studied participants free of clinical dementia, stroke, or heart failure, including 155 older adults with normal cognition and 115 mild cognitive impairment. They found that greater thoracic aortic stiffening quantified by cardiac magnetic resonance was associated with lower cerebral blood flow in cognitively normal older adults. Aortic stiffening was associated with reduced resting cerebral blood flow in the presence of preserved reactivity and associated vasodilatory capacity, particularly among participants without hypertension. ApoE4, a well-known genetic susceptibility risk factor for Alzheimer's disease, modified the results with stronger effects among carriers in the temporal lobes, where Alzheimer's disease pathology is known to first evolve. In summary, greater aortic stiffening related to lower regional cerebral blood flow and higher cerebral vascular reactivity in cognitively normal older adults, especially among individuals with increased genetic predisposition for Alzheimer's disease. Understanding the association between higher aortic stiffness and compromised brain health, including cerebral hemodynamics, may allow for earlier detection and targeted interventions to prevent or mitigate the onset of more serious cerebral vascular damage associated with greater aortic stiffening. Aortic valve replacement for aortic stenosis is usually timed according to the development of symptoms, but could the timing be too late once irreversible myocardial scar has developed? Co-first authors Drs Musa and Treibel, corresponding author Dr Greenwood from University of Leeds and their colleagues found that in patients with severe aortic stenosis, focal myocardial fibrosis determined by cardiac magnetic resonance imaging was present in over 50% of patients and was associated with a two-fold higher late mortality. Focal scar was independently associated with all cause and cardiovascular mortality, after both surgical and transcatheter aortic valve replacement. In severe aortic stenosis, late gadolinium enhancement appears to be a useful biomarker of left ventricular remodeling, and its presence is associated with worse long-term outcomes following aortic valve intervention. Thus, in severe aortic stenosis, late gadolinium enhancement may be a useful biomarker of left ventricular remodeling, and its presence may be associated with worse long-term outcomes following aortic valve intervention. The next study suggests that endogenous factor Xa activity may be irrelevant pharmacodynamic marker to guide Edoxaban dosing in future. First author Dr Yin, corresponding author Dr Giugliano from TIMI Study Group, Brigham and Women's Hospital in Boston, and their colleagues, describe the value of endogenous factor Xa activity as a pharmacodynamic marker, linking Edoxaban concentrations and clinical outcomes in the ENGAGE AF-TIMI 48 trial. They showed that the extent of inhibition of endogenous factor Xa activity was influenced by Edoxaban dosing and clinical characteristics, and was associated with both antithrombotic benefit and risk of bleeding. The implications are that this approach of linking endogenous factor Xa activity to clinical outcomes may be used to guide dose selection in future clinical trials, to monitor patients in certain clinical scenarios, or to define the doses of oral factor Xa inhibitors in patients who require precise anticoagulation therapy. The next paper describes a novel multi-protein complex that plays a critical role in regulating cardiomyocyte survival. First author Dr Zhang, corresponding author Dr Yan from University of Rochester School of Medicine and Dentistry and colleagues, showed that phosphodiesterase 1C is activated by transient receptor potential canonical channel-3 derived calcium, thereby antagonizing adenosine A2 receptor cyclic GMP signaling and promoting cardiomyocyte death or apoptosis. Targeting these molecules individually, or in combination, may represent a compelling therapeutic strategy for potentiating cardiomyocyte survival. The final paper demonstrates a molecular link between two well-recognized biomarkers of fibrosis, Galectin-3 and Osteopontin. First author Dr Shirakawa, corresponding author Dr Sano from Keio University School of Medicine and their colleagues, showed that Osteopontin was almost exclusively produced by Galectin-3 high CD206 positive macrophages, which specifically appear in the infarct myocardium after a myocardial infarct. The interleukin-10-STAT3 Galectin-3 axis was essential for Osteopontin producing reparative macrophage polarization after myocardial infarction, and these macrophages contributed to tissue repair by promoting fibrosis and clearance of apoptotic cells. These results therefore suggest that Galectin-3 may contribute to reparative fibrosis in the infarct myocardium by controlling Osteopontin levels. And that brings us to the end of this week's summaries, now for a feature discussion. Left ventricular assist devices have truly revolutionized our management of advanced heart failure. In fact, these devices have allowed us to keep patients not just as a bridge to transplantation, but as destination therapy. The devices get better and better but also more and more expensive, and the problem is, that places a lot of strain on our healthcare systems. A lot of us are crying out for information on the cost effectiveness of these newer devices, and guess what? We have answers this week with our featured paper. I am delighted to have with us the first and corresponding author Dr Mandeep Mehra from Brigham and Women's Hospital in Boston, Massachusetts, as well as our senior editor Dr Biykem Bozkurt from Baylor College of Medicine in Houston, Texas. Hello, Mandeep and Biykem! I am so pleased to be talking about a subject really close to all our hearts. Mandeep, could you start by maybe sketching out the actual issue, and maybe reminding our audience what's the difference between the different types of left ventricular assist systems that you compared. Dr Mandeep Mehra: The era of left ventricular assist devices took a major therapeutic shift when we recognized that we could usher in continuous flow devices. These are devices that generate no peripheral pulse, they do not have systole and diastole. And these devices are small in profile, have very few moving parts, and there are several commercially available devices, two in the United States and up to three worldwide, that bear these characteristics. The HeartMate II device, which is a continuous flow device that flows blood in an axial format. The HeartWare, or HVAD device, which is a centrifugal flow pump, where the blood comes in and then is ejected at a 90 degree angle. The Jarvik 2000 pump that is still used in some areas, in many regions experimentally, and then the new kid on the block, the HeartMate 3 device, which is a centrifugal flow pump with some very unique technological characteristics. Dr Carolyn Lam: Nice! And now drumroll, please tell us what you found in your brilliant study this week. Dr Mandeep Mehra: First, I'd like to remind the audience that the MOMENTUM 3 trial which randomized patients to the HeartMate II versus the HeartMate 3 device, was called MOMENTUM 3 and was a two-year study. We presented the pivotal two year trials results in 366 randomized patients earlier this year in The New England Journal of Medicine, and this study showed that the HeartMate 3 was superior on the primary endpoint when compared to the HeartMate II. The primary endpoint was survival, free of a disabling stroke, or the need to replace the pump surgically for a pump malfunction. And much of that, Carolyn, was driven by the need for replacement of the pump because the HeartMate 3 pump has some unique features that reduce its proclivity for pump thrombosis. The HeartMate 3 pump is a frictionless pump. It's completely, magnetically, dynamically, born in the rotor. It has wider blood flow paths, so we don't see hemolysis with this pump. And this pump also has an artificial intrinsic pulse that has been created, that pulsates the pump in a 40 beats per minute configuration. So this was the primary trial result, and one of the lucky foresights that we had when we designed the trial was to embed, prospectively, economic analysis within this trial. We recognized that the cost effectiveness related issues and cost configurations with these devices would become very, very important as we scale into today's day and age of healthcare transformation. And the paper that is being presented in Circulation this week, really speaks to the health resource utilization and cost outcomes between the two devices. We found that the HeartMate 3 pump is actually a cost minimization device, and what that means, Carolyn, is that we have become very used to thinking of new technology as providing incremental costs. So we think that, "Oh, well, what incremental costs should society bear for the benefits as we allocate new technology?" And in this particular trial, what we found is that while the costs of the pump itself, the HeartMate II and the HeartMate 3, were kept the same, which means its operational implant costs were the same, pretty much. We found that the HeartMate 3 pump was associated with a reduction in healthcare resource utilization over two years and with a marked decrease in cost. And in fact, our estimate of cost reduction was in the range of about 65 thousand dollars less, compared to the HeartMate II, in favor of the HeartMate 3. Dr Carolyn Lam: Wow, Mandeep, first of all, congratulations on these remarkable findings. Biykem, I really have to bring you in here. What do you think of the implications of this? Dr Biykem Bozkurt: First, I would like to congratulate the authors for a very innovative approach. As Mandeep has stated, they prospectively collected very challenging billing data from the hospitals, and then also did a very complex analysis including the VRG, as well as looking at payer reimbursements for public versus private. And did a variety of subgroup analysis, which I thought was quite helpful in sorting out that perhaps the cost effectiveness was concurrent both from the Medicare, the public, as well as the private, or regardless of the intent for destination versus bridge to transplant. Probably the most important concept when you look at these close analysis is incremental cost effectiveness ratio, per quality of adjusted life year gained. Now, I do realize the current analysis doesn't allow us to infer the ICER benefit or the incremental cost effectiveness, which I think the investigators are planning to do with a thousand and more patients over a course of two years, which is going to be probably the more definitive. But as it currently stands, with what is provided by Dr Mehra and his colleagues is, we're probably reaching that sweet spot of what is construed as the cost effectiveness ratio of a cost. Let's say 100 thousand dollars over the course of a year, then I would like to ask Mandeep whether on the prediction will reach that threshold of less than 100 thousand dollars. Because the former studies, looking at the ICER ratios, or incremental cost effectiveness ratios for the DT destination therapies, usually we select somewhere around 200 thousand dollars. And I know that usually that is seen as a prohibited cost, and there was a discussion whether we would be able to reduce the cost by about half, either doing index admission and add subsequent hospitalizations. With the data Dr Mehra and his colleagues have shown, it looks like the re-hospitalization cost is about, approximately half, or reduced by 50%. Mandeep, any thoughts on that, on that sweet spot? Dr Mandeep Mehra: Yeah. I think, Biykem, you have articulated this extraordinarily well. And for the audience, since it's worldwide, I'd like to place a few things in perspective on how to think of economic modeling. First of all, the point I would make is that this is the first prospectively collected data that we have in the field, and as you pointed out, it was very, very difficult to pull this data together and is still very complex. But let's just think about what ICER really is. It all starts with what we consider to be health utility. For example, Carolyn, Biykem, and me less so, would have a health utility of 1.0, 1.0 means a perfect health utility number. And I know, Carolyn, you and Biykem are absolutely perfect so you would be a 1.0, I probably am not a 1.0. But a patient with advanced heart failure has a health utility of about .4, so that's only 40% of what is perfect. And when we place ventricular assist devices, whether you place the HeartMate 3 or the HeartMate II, the health utility actually jumps up to about .7. So it's not perfect yet, but it moves all the way up there. The incremental cost effectiveness ratios of implanting a device over time are calculated based on this health utility benefit, compared to the population of advanced heart failure. And the best current estimates of the HeartMate II are that ICER is about 200 thousand dollars, per quality adjusted life years gained, and this has been done by creating what's known as Markov modeling. A lot of that, by the way, is conjecture, it's not real information. It is predicted information, so one has to take that data with a grain of salt. Here in this health resource analysis for MOMENTUM 3, we actually looked at actual data. There are some estimates used in this analysis as well, where we did not have accurate billing forms available, but we focused on those things where we had very clear knowledge of the cost of outcomes. For example, we did not look at the costs of outpatient follow-up care. We mainly looked at the cost differences of hospitalizations. And what we essentially found here is that just looking at hospitalizations and differences between the two devices, the cost differential, whether it's Medicare which is public [inaudible 00:20:14], or whether it's commercial. It ranges somewhere between 50 to 65 thousand dollars of difference between the two devices. Now, if you assume that the ICER for the HeartMate II is accurately at about 200 thousand, and you reduce that ICER by about 50 to 60 thousand, the ICER would naturally come into the range of what you would consider to be about 135 thousand to 150 thousand dollars per quality adjusted life years gained for the HeartMate 3, compared to an advanced heart failure population. Once we look at it from that perspective, as Biykem pointed out, we are getting closer and closer to the societal norms. At one time-point, society used to think of a quality adjusted life years gained cost of 50 thousand dollars as something that would be acceptable to society, and this was seemingly based on the threshold for what dialysis provides in benefit. And now, we recognize that we have to really expand that to somewhere around 100 thousand more logically, or between 100 and 150 thousand for some technologies. The important thing I would say to you is that, that is society dependent. So what the United States considers to be a reasonable ICER, say 100 to 130 thousand dollars per quality adjusted life years gained, may not be the same that Great Britain would look at, or Sweden would look at, or another country would look at. And each country actually creates their own economic value propositions, and this will have to be taken into account as we think about this data as well. Dr Carolyn Lam: How cleverly and clearly articulated, thank you so much Mandeep. Just one last question for both you and Biykem, what do you think this implies for moving to less and less advanced heart failure with these left ventricular assist device systems? Biykem? Dr Biykem Bozkurt: It's an ever-expanding field, and as these devices are becoming smaller, lower profile with lesser complications and more affordable, probably the utilization will likely increase as we have been seeing. As you know, even the percutaneous non-durable device used, as well as our mechanical circulatory support durable devices are definitely increasing utilization. And thus, one may wonder not only the bridge to transplantation, but the destination therapy portfolio, or bridge to decision portfolio, may really increase as these devices become safer and more affordable. Dr Carolyn Lam: Wow, that's amazing. How about you, Mandeep, what do you think? Dr Mandeep Mehra: Carolyn, I couldn't have said it any better than what Biykem articulated. I do think that at least in the United States, as we reach the thresholds of cost effectiveness that we as a society accept, we will start to see a lot more widespread utilization, particularly for lifelong therapy or so-called destination therapy. I completely agree with that. I think that moving the needle to the less sicker population is still challenging, because there are complications with these devices that make that slightly difficult. There was a trial called the REVIVE-IT trial that was stopped midstream largely because of concerns about pump thrombosis, and that trial was looking at taking these devices to a less sick NYHA class 3 population and was stopped midstream. Now that the HeartMate 3 has pretty much resolved the issue of pump thrombosis, and even show a halfing in stroke rates with this device over two years, I think that that portfolio of evidence needs to be reopened. I would caution though, that until we have confirmatory randomized data in those less sick populations, the use to that population should still stay restricted. Dr Carolyn Lam: I don't think anyone could have said it better than both of you. Thank you so much for this very insightful and balanced conversation. Thank you so much for listening today. You were listening to Circulation on the Run, and don't forget to tune again next week.
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Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. This week's journal is really special. It is the 2017 cardiovascular surgery-themed issue of "Circulation." To summarize this issue, I am so privileged to have the editors, Dr. Marc Ruel from University of Ottawa Heart Institute, as well as Dr. Timothy Gardner from Christiana Care Health System. Welcome gentleman. Dr. Timothy Gardner: Hello. Dr. Marc Ruel: Hi, Carolyn. Glad to be here. Dr. Carolyn Lam: Thank you for another beautiful themed issue, Marc. I see that there are four general themes within this theme, if I may. The first of which are a collection of papers on coronary disease and coronary surgery. Could you maybe start by giving us an overview of that? Dr. Marc Ruel: One of the main topics that have been looked at in the surgical-themed issue this year is coronary surgery. We all know well that 2016, 2017, the academic year was quite fertile in providing new information around coronary surgery, especially with the release of the ART trial had actually scientific sessions of the American Heart Association the last November with simultaneous publication. Interestingly, the cardiovascular surgical-themed issue has several coronary papers and one that deals with essentially with graft failure, if you will. There's an in-depth review written by Mario Gaudino, who is well known and does fantastic work at Cornell, who essentially put a team together looking at several aspects of coronary graft failure. I guess we can say that these are looked in quite great depth, and they deal with several aspects of what would lead to a coronary bypass graft to fail. First and foremost, Mario and the team look at the blood components. Then the artery and the native bed itself. Then they focus a lot on the conduit, not only the nature of the conduit being a venous versus arterial conduit, but also the way of storing the conduit prior to performing the bypass. Also, the technique that's used around the use of that conduit. Finally, I'd say that the review culminates with the patient bioreactor, for lack of a better term, aspect. Endothelial dysfunction in the patient with diabetes, age, gender, hypertension, dyslipidemia, etc., all these things that do act as a significant substrate for the fate of the conduit vessel. A very unique, I think, first-time, in-depth review that, certainly, the "Circulation" editorial team and reviewers were very excited about. I think this will be quite impactful and provide very, very detailed information for future research and future improvement and fate of the coronary graft conduits. Dr. Carolyn Lam: And, Dude, I agree. It's the new look at perhaps a classic, old, central surgery, the cardiovascular surgery. Very nice, indeed. Dr. Marc Ruel: Precisely, thank you. We also have a couple of important, seminal original papers within the realm of coronary surgery. In fact, these also deal, to some extent, with the fate of conduits and certainly how they work in the patient population in long ago bypass surgery. One is a randomized control trial, a single center randomized control trial that was performed in South Manchester. It's called the VICO trial, a study comparing vein integrity and clinical outcomes. Essentially, the study looked at open vein harvesting versus two types of endoscopic vein harvesting for coronary artery bypass grafting. The study was performed at a single center in England with three sound methods, having three groups of 100 patients who were compared with regards to the vein harvest technique. The primary outcome was with regards to actual vein integrity, looking at muscular damage and endothelial function and integrity on microscopy. Surprisingly and actually quite reassuredly that there were very few differences between endoscopic vein harvest and open vein harvest. Certainly the investigators also looked, as one of their secondary outcomes, at quality of life. It was quality of life that was gained in patients who had endoscopic vein harvest versus those who had open vein harvest. Overall, there was no difference in major adverse cardiac events. Therefore, showing at least in an internally valid fashion that these investigators at their center could do endoscopic vein harvesting as well as open vein harvesting. Dr. Carolyn Lam: I know that there are other original research papers, perhaps. Would you like to highlight any of them? Dr. Marc Ruel: Yes, for sure. Carolyn, there's also one more coronary surgery paper, which I wanted to highlight and that is the paper entitled, "Does Use of Bilateral Internal Mammary Artery Grafting Reduce Long-Term Risk of Repeat Coronary Revascularization?" This is a multi-center analysis with first author is Iribarne from Northern New England. Essentially, seven medical centers got together and took about 20 years of consecutive CABGs with a total number of 50,000 operations, or just shy of 50,000 operations. The median duration of follow-up was 13 years, and these patients were well matched together using a propensity matching scheme. I think this paper and this research is unique and of high impact. Even though it does have shortcomings of not being a randomized control trial, it is very welcome information, especially in light of the recent ART trial, which, as you know, did not show any difference at five years analysis between single and bilateral internal thoracic artery use. The particularity of the Iribarne paper is that it is a very large data set up with close to 50,000 patients. It is multi-centered, therefore, it is real life. It is a consecutive series. The patients are extremely well matched, and it is remarkable to hear that the patients, in fact, had no difference in mortality until about five years after the operation. As opposed to many previous series where single versus bilateral internal mammary grafting shows a mortality difference very early on, which always raises the suspicion of poor matching or confounding by indication, if you will, this paper did not have that. Finally, the follow-up was quite long and at about six years, there was really a mechanistic signal with regards to repeat revascularization events, which seemed to match the difference in late mortality. There was no difference in early and five-year mortality, but afterwards as repeat revascularization events started to occur more frequently in the single mammary group, this was matched by a difference in mortality, as well. I think a very useful, large, long follow-up mechanistically-based information that I think adds very significantly to the current information we have about bilateral versus single mammary use. Dr. Carolyn Lam: Thank you, Marc. Two original papers, highlighted, dealing with really very important modern controversies in this area. Open vein versus endoscopic vein harvesting, single versus bilateral mammary artery bypass. Excellent. Let's move on now to the next sub-theme, if you will. And that is the collection of papers on "Adult Congenital Heart Conditions," really, really an increasingly important and growing population that we're seeing. Tim, would you like to summarize maybe some of the highlights of the papers there? Dr. Timothy Gardner: The first paper, as you point out, is focused on adult patients with repaired tetralogy of Fallot. This series came from the UK and it examines the course of almost 60 patients, at a mean age of 35 years following a repair of tetralogy as infants or young children, developed right heart failure and required pulmonary valve replacement. This is a common scenario that we're seeing, successfully repaired children who appear to do well but as they get into their late 20s and 30s, their pulmonary valve function, which is often inadequate or not even present valve, require an intervention. The important learning here is that pulmonary valve replacement, either surgically or by catheter technique, was shown to be highly effective in salvaging right ventricular function. That is based on imaging studies as well as hemodynamic studies of right ventricular function. There was an almost, in this group of patients, almost an immediate reverse remodeling of the right ventricle after placement of the valve, that continued to improve over time. This was, I think, quite reassuring. There, historically, was a bit of a reluctance to operate on these patients as their right heart was failing, despite the fact that without some intervention to take the volume load off of the RV, the patients didn't do well. This is good news for an important group of patients who we are all seeing, who oftentimes present to the adult cardiologist because of this right ventricular failure problem. A nice, reassuring study. Actually, the other two congenital papers are, again, focused on the infant. They both deal with the infant with hypoplastic left heart syndrome or single ventricle pathology. The first paper seems sort of specialized in terms of its focus, "The Optimal Timing of Stage-2-Palliation for Hypoplastic Left Heart Syndrome." This was a report from the NIH Pediatric Heart Network. They had a single ventricle reconstruction trial. This network is comprised of about 10 North American centers, both in the U.S. and Canada and has provided excellent data about the management of pediatric heart disease but, in particular, the single ventricle trial has been excellent. In this particular paper, they look at the optimal timing for stage-2 repair. Just to remind ourselves, the first part of the three-stage treatment for hypoplastic left heart syndrome is the Norwood procedure, which has to be done shortly after birth, as the patent ductus arteriosus closes and converts, essentially, the single right ventricle into the systemic ventricle. The stage-2 comes along, usually done with a Glenn-type of shunt, increases pulmonary blood flow and stabilizes these infants until they can reach the age for, and the heart function for definitive repair. This has been a particularly difficult problem for the congenital heart surgeons. What is the optimal timing? This study, which involved over 400 patients, identified optimal timing for the second stage between three and six months after the Norwood. I think this was very reassuring, is reassuring or supportive for the congenital heart community in terms of both patients and also good evidence base that a delay of three to six months does, in fact, produce the best transplant-free survival. In fact, the other aspect of this observation was that infants who developed the need for another second stage operation sooner than that did not do well, and the reasons for the required earlier surgery could be failure of the initial operation or additional anatomic risk factors. But this, I think, was an important, large series, multi-center study that will prove to be very helpful in sorting out this complex timing of a three-stage repair. Just to comment, again, for readers who don't deal with infant congenital heart treatments very often, there's been a remarkable amount of success over the last two decades in salvaging and saving these very difficult infants with the hypoplastic left heart syndrome. In fact, an additional paper in this surgery-themed issue, comes from the UK and is, in fact, a report on the findings from the UK-wide audit of the treatment of infants with hypoplastic left heart syndrome. In fact, their findings, in this sort of real world, not in the Pediatric Heart Network trial group, is very similar. They found that infants who got to the second stage without additional refinement of the initial Norwood procedure and were able to be successfully treated with a Glenn shunt somewhere in the four-to-six-month age range, did well. They actually made the point that the anatomy was more of a determinant than anything else. I think that this particular review will reinforce what the congenital heart surgeons have learned about optimal timing for this three-stage treatment of what previously were unreconstructable children. Dr. Carolyn Lam: Thank you so much, Tim. Isn't it wonderful the way papers come in and they're actually complementary and consistent with one another. We're just so lucky to be publishing all of these great, high-quality, impactful papers in "Circulation." Moving on, the next paper actually reminds us why this is a cardiovascular surgery-themed issue and not just a cardiac surgery-themed issue. Didn't we just say that earlier, Marc? This one is on abdominal aortic aneurysm treatment. A population-based landscape of this. Could you tell us a little bit more about that one? Dr. Marc Ruel: Absolutely. Carolyn, you're entirely right. We must remember that "Circulation" is also about peripheral vascular disease, saying this earlier, or cardiovascular surgery and anesthesia consult also when it encompasses vascular surgery. Precisely to that effect, one of the papers in our cardiovascular surgical-themed issue is a landscape population based analysis from Finland that looks at the incidence of abdominal aortic aneurysm between the years of 2000 and 2014. Finland has a population of about 5.5 million and remarkably has a very circumscribed healthcare system. They do not have an organized system of AAA care as some other countries have shown to have and potentially benefit from, but rather they have a treatment of this condition at several institutions, many of which may not be high volume. I think the paper is remarkable is that it is very well nested in terms of a population. It provides a comprehensive landscape of where this condition has evolved to over the last few years. Obviously, we see in the results from the authors that the mortality has decreased quite a bit, but also the incidence, probably as a result of better control of risk factors. And also the incidence of rupture outside the hospital. One thing that came out of this paper, as well, is a potential cohort of the benefits gained from developing an organized system of AAA care, from the reason that the mortality of AAA rupture in Finland was still quite high, despite this being a modern series. In fact, when you include ruptures, before arrival to hospital and at arrival to hospital, the overall mortality was almost 80% for ruptured AAA. Perhaps one message that comes out of this is that there may be a benefit in having specialized centers dealing with these conditions, especially as they are in the process of rupturing. One last observation was, obviously, the increasingly prevailing role of endoscopic vascular repair in the treatment of this condition, which, in fact, has now surpassed open repair as the dominant method of elective repair. I think, overall, a very comprehensive, well-nested, country-wide with good follow-up landscape of the AAA condition in a country that has essentially a similar socioeconomic status to much of the western world. Therefore, with external generalized ability to some extent. Dr. Carolyn Lam: Exactly, and contemporary data. I really enjoyed that you paired those with an excellent editorial, as well. Finally, before we wrap this up, I have to ask Tim to comment on this next paper, and it's on ventricular assist device malfunctions, I love the title, "It's More Than Just The Pump." Of course, as a heart failure physician, this one's very close to my heart. Forgive the pun. But, Tim, could you tell us about that? Dr. Timothy Gardner: This paper comes from the University of Pittsburgh and their artificial heart program. Robert Kormos is the first author and he's been one of the stalwart leaders in the use of LVADs and other pump devices. He reports on their experience with over 200 both HeartMate and HeartWare ventricular assist devices. It was interesting when we reviewed this paper by the editors, there was some thought that maybe this was a little too engineering focused and so on, but I think the point of the paper is that, as they say in the very first line in their report, reports of LVAD malfunction had focused on pump thrombosis. But they point out very appropriately that, in fact, controller failure, battery failure, cable failure and other causes of device failure, which can be critical and life threatening and so on, are engineering issues. It reminds us that when we're managing this difficult group of patients, and we're seeing many more patients today with getting LVADs than 10 or 20 years ago, we need to have the bioengineering abilities and resources available. Even the surgeon and the critical care physician who is dealing with these patients either has to acquire this kind of knowledge or capacity himself or herself, or needs to have a good bioengineer nearby. What's interesting, I think, that all of us define that these mechanical failures were more common in this pretty big experience than what we've more clinically worried about, which was thrombosis of the pump. Dr. Carolyn Lam: Exactly. That's so wonderful. And you know it just leads me to really thank you both, Marc and Tim, for this extraordinarily excellent selection of original research, state-of-the-art and perspective articles and editorials on congenital, coronary, vascular and heart failure surgery. This really appeals not just to the cardiovascular surgeons but really to the vast readership of "Circulation." Thank you for a wonderful themed issue and thank you for this great podcast. Dr. Timothy Gardner: Well, thank you. Dr. Marc Ruel: Thank you very much, Carolyn. Dr. Carolyn Lam: Listeners, don't forget to tune in again next week.
Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. In just a moment we'll take a deep dive into hemo-compatibility-related outcomes in the MOMENTUM 3 trial of a fully magnetically levitated pump in advanced heart failure. But first, here's your summary of this week's journal. The first paper sheds light on the biological mechanisms underlying cardioprotective effects of the Mediterranean diet. First author, Dr. Wang, corresponding author Dr. Hu and colleagues of Harvard, TH Chan, School of Public Health in Boston, Massachusetts studied 980 participants from the PREDIMED Trial including 230 incident cases of cardiovascular disease and 787 randomly selected participants at baseline followed up for 7.4 years. Participants were randomized to a Mediterranean diet supplemented with extra virgin olive oil, a Mediterranean diet supplemented with nuts, or a controlled diet. Plasma ceramide concentrations were measured and the primary outcome was a composition of non-fatal acute myocardial infarction, non-fatal stroke or cardiovascular death. The authors found a novel positive association between baseline plasma ceramide levels and incident cardiovascular disease. In addition, the association between baseline ceramides and incident cardiovascular disease varied significantly by treatment groups where a Mediterranean dietary intervention appeared to mitigate the potential deleterious effects of elevated plasma ceramide concentrations on cardiovascular disease. These findings, therefore, strengthen the evidence base for recommending the Mediterranean diet for cardiovascular disease prevention and suggest that plasma ceramides have the potential to serve as markers of future cardiovascular disease risk. The next paper describes a novel therapeutic approach against hypertensive cardiac remodeling and provides the first evidence of the cardio protective effect of cardiofibroblast-specific activating transcription factor 3 or ATF3. In this study from first author Dr. Li, co-corresponding authors, Dr. Du from Beijing Anzhen Hospital in China, and Dr. Ma from Thomas Jefferson University in Philadelphia and colleagues, the authors used a discovery-driven unbiased approach to identify increased ATF3 expression in mirroring hypertensive hearts and the human hypertrophic heart, expressed primarily by cardiac fibroblast cells. ATF3 knockout markedly exaggerated the hypertensive ventricular remodeling, a state rescued by lentivirus mediated microRNA aided cardiac fibroblast selective ATF3 over-expression. Conversely, cardiac fibroblast specific ATF3 over-expression significantly ameliorated ventricular remodeling and heart failure. The authors further identified MAP2K3 as a novel ATF3 target, and that p38 was the downstream molecule of MAP2K3, mediating the profibrotic hypertrophic effects in ATF3 knockout animals. In summary, this study provides the first evidence that ATF3 up-regulation in cardiac fibroblasts in response to hypertensive stimuli, protects the heart by suppressing MAP2K3 expression, and subsequently p38 TGF-beta signaling. Thus, identifying molecules mimicking endogenous ligands or inhibiting microRNA that down-regulate ATF3 expression, may represent novel therapeutic approaches against hypertensive cardiac remodeling. These, and other issues, are discussed in an accompanying editorial by Dr. Jennifer Davis of University of Washington. The next paper tells us that clinical frailty score may need to be part of the pre-operative assessment of patients undergoing transcatheter aortic valve replacement, or TAVR. First author, Dr. Shimura, corresponding author, Dr. Yamamoto and colleagues of Toyohashi Heart Center in Japan, utilized the optimized catheter valvular intervention or OCEAN Japanese Multicenter Registry of 1215 patients undergoing TAVR and found that clinical frailty score correlated with other markers of frailty, such as body mass index, albumin, gait speed and grip strength. Furthermore, the clinical frailty score was an independent predictive factor of increased late-cumulative mortality risk. Thus, in addition to reflecting the degree of frailty, the clinical implications of these findings are discussed in an accompanying editorial by Dr. Jonathan Afilalo from McGill University in Montreal. In the final study, we learned that long-term anabolic androgenic steroid use may be associated with myocardial dysfunction and accelerated coronary atherosclerosis. Dr. Baggish and colleagues from Massachusetts General Hospital in Boston, used a cross-sectional cohort design of 140 experienced male weight lifters, age 34-54 years, comprising 86 men reporting at least two years of cumulative lifetime anabolic androgenic steroid use, and 54 non-using men. Compared to non-users, steroid users demonstrated relatively reduced left ventricular systolic function and diastolic function on transthoracic echocardiography. Furthermore, steroid users demonstrated higher coronary artery plaque volume on coronary CT angiography compared to non-users. In summary, this is the first large controlled study of its type to demonstrate that long-term anabolic androgenic steroid use is associated with both systolic and diastolic myocardial dysfunction, as well as coronary atherosclerosis. Thus, when clinicians encounter young or middle-aged men who exhibit evidence of unexplained left ventricular dysfunction or premature coronary artery disease, the possibility of cardiotoxicity due to long-term anabolic androgenic steroid use should be considered in the differential diagnosis. Well, those were your summaries. Now, let's move on to our featured discussion. For our featured discussion today, we are actually reviewing a secondary analysis of the MOMENTUM 3 Trial, which is a multicenter study of the mag lev technology in patients undergoing mechanical circulatory support, with the HeartMate 3. And to discuss today's findings I'm so pleased to have the corresponding author, Dr. Mandeep Mehra from Brigham and Women's Hospital in Boston, Massachusetts, as well as Dr. Biykem Bozkurt, Associate Editor from Houston, Texas. Welcome Mandeep and Biykem. Dr. Mandeep Mehra: Thank you. It's a pleasure to be with you all. Dr. Biykem Bozkurt: Thank you. Dr. Carolyn Lam: Let's start by getting a few definitions right, shall we, just for our audience. This specific article, and congratulations Mandeep, it's just so great, it speaks of hemo-compatibility-related outcomes. Could you start by telling us what that is, and maybe reminding us what the original MOMENTUM 3 short-term results showed. Dr. Mandeep Mehra: Sure. As our listeners are aware, left ventricular assist devices have really transformed the management of refractory advanced heart failure, by the introduction of a form of flow, called continuous flow, in the devices, which tend to render patients, relatively low pulsatiles to non-pulsatile. Now what we've seen is that the interface between this very unnatural physiology from continuous flow in concert with the patient's biology tends to create a constellation of problems that we sort of refer to as hemo-compatibility-related adverse events. For example, we have seen a very curious development of recurrent gastrointestinal bleeds that tend to occur in a manner similar to what was observed with critical aortic stenosis, the so-called Heyde's Syndrome. Similarly we see stroke-related problems and we also see evidence of thrombosis that can sometimes develop within the pump. So we refer to the conglomeration of these unique complications that arise from the abnormal interface between the device and the patient as hemo-compatibility-related adverse events. Dr. Carolyn Lam: And this is a secondary analysis, a six-month secondary analysis, right? So could you give a little bit of background of why you would hypothesize that these events might be different with the HeartMate 3 versus 2? I mean, it's quite unique that we're going back to creating a pulse. Dr. Mandeep Mehra: Yes. Let me fist define for our audience what the MOMENTUM 3 Trial was designed to initially do, and is still doing. MOMENTUM 3 is a randomized controlled trial of two devices: one, a conventionally available continuous flow device called the HeartMate 2, and the second device, the novel pump called the HeartMate 3. The HeartMate 3 is a pump that took two decades to engineer. And it took that long because it is very unique, based on the following principles. First, it's a small profile, so the entire pump can be placed intrathoracically. Second is that the way in which it moves blood, its rotor, is fully magnetically levitated, which means that it has no friction when it rotates. The third is that despite its small profile, this device has wide blood flow gaps, meaning that as blood is moving in this centrifugal flow pump, it does not expose the blood elements to as much of sheer stress as one sees with other conventionally available devices. And then finally, what this device has uniquely is a intrinsic pulse, and what that means is that we program this device in a fixed program to actually ramp its speed up and ramp it down so that it creates an intrinsic pulse of about 30 beats per minute, which is engineering-wise designed to improve pump wash out; that's the intention. So the MOMENTUM 3 Trial was constructed to really compare these two devices and we recently reported, on the primary end point of the six-month outcomes of this trial. And the trial primary end point was set at survival free of a disabling stroke, or the need for re-operation because of pump malfunction. And what we found was that this pump, the HeartMate 3, clearly met its non-inferiority end point, versus the HeartMate 2, but also demonstrated superiority on the primary end point at six months. We were certainly not expecting to see superiority at this early time point, but we were very fortunate to see that. Now what is unique about this is that for the first time ever, we saw no cases of suspected or manifest established pump thrombosis, as a result of de novo pump thrombosis requiring re-operations with the HeartMate 3 device. And this is a frequency of about 10% that we normally observe with pumps. That is one in 10 pumps will clot off within about six months, and require re-operation. So we were very gratified to see this observation in the short-term data of the primary MOMENTUM 3 database. Now as a result of that observation, Carolyn, we thought that the hard end points, as are typically adjudicated for the primary basis of these clinical trials, missed the entire constellation of hemo-compatibility-related outcomes because these are patients who develop both bleeding and clotting complications. And the net burden of hemo-compatibility is not entirely available for review, which is the basis of this important secondary analysis that was published in Circulation. Dr. Carolyn Lam: What striking findings. So tell us the bottom line. Dr. Mandeep Mehra: What we found in the secondary analysis was evidence that the burden of hemo-compatibility-related adverse events is lower in patients with the HeartMate 3, compared to the HeartMate 2 device. And that was the basis of the bottom line that we found. In particular, we knew that there were no episodes of de novo pump thrombosis with the HeartMate 3, but we also found that there was evidence of a reduction in non-disabling strokes with the HeartMate 3 device. So we now have evidence that thrombotic complications, minor strokes, as well as pump thrombosis, seem to be abrogated by this new pump. What we should keep in mind, however, is that this is still early data from the ongoing MOMENTUM 3 Trial, and the trial is actually designed to enroll and observe over a thousand patients, over two years. And we are basically showing in this a very early look at six months of about 300 of these patients. And so that needs to be kept in mind. But we are extremely encouraged by these early trends suggesting that we may have started to break the issues related to the barriers of implementation of such therapy in the hemo-compatibility domain. Dr. Carolyn Lam: Yeah, and as a heart failure doc, I can tell you that I share that excitement and I know that Biykem does too, as did the editors. Biykem, tell us a little bit about what we talked about as editors about this paper. Dr. Biykem Bozkurt: Indeed. Mandeep, the hemo-compatibility concept which is being addressed in this new publication is quite novel and is exciting, and addresses the continual spectrum of the pathology, ranging from the GI bleed, to the stroke spectrum. The question I have, in this study, the overall scores were not different in the absolute number that we saw as a score from the hemo-compatibility ranking. Do you think we would continue to use this approach as a quantitative score, given the fact that there may be bidirectional impact from different devices on the different spectrum, especially with the recognition that HeartMate 3 seemed to be protective against the thrombotic, perhaps events, or should we use it more of a qualitative score card looking at which perhaps spectrum the device tends to be a little bit more risky or beneficial. So shall we color code this score and try to perhaps focus on the spectrum of thrombosis versus bleeding and then try to strategize? Dr. Mandeep Mehra: Thank you for that very erudite question, Biykem. You hit right at the heart of the matter. So let me make a few comments about that. The first issue is that so far, the field has not had a clear definition of hemo-compatibility. Hemo-compatibility has been more of a engineering term. When someone said hemo-compatibility, they thought of biomaterials, rather than a clinical definition of hemo-compatibility. So for the first time, we have actually introduced the term hemo-compatibility into the lexicon of definition, managing patients with LVAD, so that's one important point. The second important point is that we, until this day, until this analysis, have not had the ability to really provide people with a full picture of the entire burden of experience of hemo-compatibility-related complications that an individual patient experiences as they are on this device, because you know that patient's going to have a GI bleed, and then they may have a stroke, because we may change, dynamically we may change anticoagulation for instance if someone has one event then the other, and the traditional way in which studies are done, hey do not give you a clear picture into the burden of hemo-compatibility. So the most innovative thing about this clinical hemo-compatibility definition, is that we've not introduced a score that reflects the burden of disease, and we have also created tiers of severity of the burden of disease experience into three quantitative tiers that include various subsets which are hierarchal. So for example, is one gastrointestinal bleeding the same as non-disabling stroke? Well, no. One gastrointestinal bleeding may be a milder form a hemo-compatibility-related problem. So our early look at this clearly shows that survival free of a hemo-compatibility-related event is clearly lower in the patients with a HeartMate 3. However, as you astutely pointed out, when you examine purely the burden of hemo-compatibility-related complications experienced by the survivors, one actually sees a trend in favor of the HeartMate 3, but not a statistically significant difference, largely because we have not yet abrogated problems related to bleeding complications on the side of the hemo-compatibility. Why is that? Well, it's because we still treat all patients in both groups with the HeartMate 2 or the HeartMate 3 with the same intensity of anticoagulation. What this sort of data points out to us in the future, first of all, is that it allows us to compare apples to apples, as we are looking at different device platforms, that's number one. Second is it gives a much more robust look into the total patient experience. And third, it actually gives us insight into whether altering one component of the equation, so let's say there's a bleeder, if you actually react to that clinically, will you start to see problems on the clotting side. Dr. Biykem Bozkurt: This is a very, very important study that addresses the whole spectrum of hemo-compatibility in a more comprehensive fashion, and also points out perhaps the differences that we see in overall others, centrifugal flow, left ventricular assists, support systems such as the Heartware HVAD study that showed increase in hemorrhagic stroke, especially hemorrhagic stroke in the first six months in the ENDURANCE Trial, whereas the HeartMate 3 has shown in the MOMENTUM 3 publication, as well as the Circulation secondary end point study demonstrates a reduction in disabling strokes and absence of any pump thrombosis. So there are differences, despite both of the pumps are centrifugal, there are differences in the profile, and the spectrum of the risk and hemo-compatibility. And one other interesting finding from this study is that the predictors for hemo-compatibility outcomes are complementary to what has been known in the sense that lower antiplatelet and anticoagulation management strategies are associated with increased risk of hemo-compatibility adverse events. And surprisingly, the control of blood pressure did not appear to correlate with the hemo-compatibility outcomes. So from that perspective, it differs from the ENDURANCE Trial where the uncontrolled blood pressure or hypertension was associated with hemorrhagic strokes, in the ENDURANCE Trial, whereas in the MOMENTUM 3, the blood pressure did not appear to correlate with the hemo-compatibility outcomes or pump thrombosis. So these are very interesting findings and I think are complementary to the evolving field of the risk benefit ratios in patients with LVAD support. And from that perspective, we in Circulation felt that this will be a very valuable publication for our readership as well as for the whole heart failure and transplant community. Dr. Carolyn Lam: Thank you, so much for joining us today, don't forget to tune in next week.
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