Podcasts about transthyretin

CardioNerds Cardiac Amyloidosis Series Chair Dr. Rick Ferraro and Episode Lead Dr. Anna Radakrishnan discuss the biology of transthyretin amyloid cardiomyopathy (ATTR-CM ) with Dr. Daniel Judge.  Notes were drafted by Dr. Anna Radakrishnan. The audio was engineered by student Dr. Julia Marques.  This episode provides a comprehensive overview of transthyretin (ATTR) cardiac amyloidosis, a complex and rapidly evolving disease process. The discussion covers the key red flags for cardiac amyloidosis, the diagnostic pathway, and the implications of hereditary versus wild-type ATTR. Importantly, the episode delves into the current and emerging therapies for ATTR, including stabilizers, gene silencers, and promising treatments like CRISPR-Cas9 and antibody-based approaches. Dr. Judge shares his insights and excitement about the rapidly advancing field, highlighting the need for early diagnosis and the potential to improve long-term outcomes for patients with this condition.  Enjoy this Circulation Paths to Discovery article to learn more about the CardioNerds mission and journey.  US Cardiology Review is now the official journal of CardioNerds! Submit your manuscripts here.  CardioNerds Cardiac Amyloid PageCardioNerds Episode Page Pearls: - Biology of Transthyretin amyloid cardiomyopathy Maintain a high index of suspicion! Look for subtle (yet telling) signs like ventricular hypertrophy, discordant EKG findings, bilateral carpal tunnel syndrome, and spontaneous biceps tendon rupture.  Utilize the right diagnostic tests. Endomyocardial biopsy remains the gold standard, but non-invasive tools like PYP scan with SPECT imaging and genetic testing are essential for accurate diagnosis.  Differentiating hereditary from wild-type ATTR is critical, as genetic forms may have a more aggressive course and familial implications.  Early diagnosis and intervention significantly improve prognosis, making vigilance in screening and prompt treatment initiation essential.  The future is now! Cutting-edge therapies are transforming the treatment landscape, including TTR stabilizers, gene silencers, and emerging technologies like CRISPR-Cas9 and antibody-based treatments.  Notes - Biology of Transthyretin amyloid cardiomyopathy What is transthyretin amyloid (aTTR) and how is it derived?  Transthyretin (TTR) is a transport protein primarily synthesized by the liver, responsible for carrying thyroid hormones (thyroxine) and retinol (vitamin A) in the blood. It circulates as a tetramer, composed of four identical monomers, which is essential for its stability and function.  In transthyretin amyloid (ATTR) amyloidosis, the TTR protein becomes unstable, leading to its dissociation into monomers. These monomers misfold and aggregate into insoluble amyloid fibrils, which deposit extracellularly in tissues such as the heart, nerves, and gastrointestinal tract. This progressive amyloid deposition leads to organ dysfunction, including restrictive cardiomyopathy and neuropathy.  There are two main forms of ATTR amyloidosis: hereditary (variant) and wild-type (senile) ATTR.  Hereditary ATTR (ATTRv) is caused by mutations in the TTR gene. These mutations destabilize the TTR tetramer, making it more prone to dissociation. This increases misfolding and amyloid fibril formation, resulting in systemic amyloid deposition.   Wild-type ATTR (ATTRwt) occurs without genetic mutations and is primarily age-related. Over time, even normal TTR tetramers can become unstable, leading to gradual misfolding and amyloid deposition, particularly in the heart. ATTRwt is a common but often underdiagnosed cause of heart failure with preserved ejection fraction (HFpEF) in elderly individuals.  How does aTTR lead to deleterious effects in the heart and other organ systems?    Transthyretin amyloidosis leads to organ dysfunction through the deposition of misfolded TTR protein as amyloid fib...

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/NCPD/CPE information, and to apply for credit, please visit us at PeerView.com/QTM865. CME/NCPD/CPE credit will be available until January 22, 2026.Don't Fail Them Now: Bridging Diagnostic and Treatment Gaps in Transthyretin Cardiac Amyloidosis[JAC_Logo] In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from BridgeBio Pharma, Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/NCPD/CPE information, and to apply for credit, please visit us at PeerView.com/QTM865. CME/NCPD/CPE credit will be available until January 22, 2026.Don't Fail Them Now: Bridging Diagnostic and Treatment Gaps in Transthyretin Cardiac Amyloidosis[JAC_Logo] In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from BridgeBio Pharma, Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/NCPD/CPE information, and to apply for credit, please visit us at PeerView.com/QTM865. CME/NCPD/CPE credit will be available until January 22, 2026.Don't Fail Them Now: Bridging Diagnostic and Treatment Gaps in Transthyretin Cardiac Amyloidosis[JAC_Logo] In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from BridgeBio Pharma, Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/NCPD/CPE information, and to apply for credit, please visit us at PeerView.com/QTM865. CME/NCPD/CPE credit will be available until January 22, 2026.Don't Fail Them Now: Bridging Diagnostic and Treatment Gaps in Transthyretin Cardiac Amyloidosis[JAC_Logo] In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from BridgeBio Pharma, Inc.Disclosure information is available at the beginning of the video presentation.

Commentary by Dr. Sabahat Bokhari.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/NCPD/CPE information, and to apply for credit, please visit us at PeerView.com/QTM865. CME/NCPD/CPE credit will be available until January 22, 2026.Don't Fail Them Now: Bridging Diagnostic and Treatment Gaps in Transthyretin Cardiac Amyloidosis[JAC_Logo] In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from BridgeBio Pharma, Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/NCPD/CPE information, and to apply for credit, please visit us at PeerView.com/QTM865. CME/NCPD/CPE credit will be available until January 22, 2026.Don't Fail Them Now: Bridging Diagnostic and Treatment Gaps in Transthyretin Cardiac Amyloidosis[JAC_Logo] In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from BridgeBio Pharma, Inc.Disclosure information is available at the beginning of the video presentation.

Are you up to date on the new developments for emerging therapies for your patients with transthyretin amyloid cardiomyopathy (ATTR-CM)? Credit available for this activity expires: 12/16/25 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/1002007?ecd=bdc_podcast_libsyn_mscpedu

Host: John Russell, MD Guest: Noel Dasgupta, MD, FACC Guest: Sami Khella, MD Amyloidosis, often unrecognized, misdiagnosed, and either inappropriately treated or undertreated, is a collection of diseases caused by the misfolding of proteins that aggregate into insoluble amyloid fibrils and deposit in tissues. There are two prominent forms of amyloidosis misfolding of light chain proteins (AL amyloidosis) and transthyretin protein misfolding (ATTR amyloidosis). In this program, two experts in amyloidosis, cardiologist Dr. Noel Dasgupta and neurologist Dr. Sami Khella, will explain the pathophysiology of amyloidosis, describe the prognosis for patients, discuss timely patient screening and diagnostic testing, and provide updated treatment options.

CME credits: 0.50 Valid until: 13-12-2025 Claim your CME credit at https://reachmd.com/programs/cme/best-practices-for-identifying-diagnosing-and-treating-transthyretin-amyloidosis-attr-pn-and-attr-cm/26799/ Amyloidosis, often unrecognized, misdiagnosed, and either inappropriately treated or undertreated, is a collection of diseases caused by the misfolding of proteins that aggregate into insoluble amyloid fibrils and deposit in tissues. There are two prominent forms of amyloidosis misfolding of light chain proteins (AL amyloidosis) and transthyretin protein misfolding (ATTR amyloidosis). In this program, two experts in amyloidosis, cardiologist Dr. Noel Dasgupta and neurologist Dr. Sami Khella, will explain the pathophysiology of amyloidosis, describe the prognosis for patients, discuss timely patient screening and diagnostic testing, and provide updated treatment options. =

Zaeem Siddiqi, MD, PhD - Tailoring Treatment for Hereditary Transthyretin Amyloidosis Polyneuropathy: The Evolution of Care

Zaeem Siddiqi, MD, PhD - Tailoring Treatment for Hereditary Transthyretin Amyloidosis Polyneuropathy: The Evolution of Care

Zaeem Siddiqi, MD, PhD - Tailoring Treatment for Hereditary Transthyretin Amyloidosis Polyneuropathy: The Evolution of Care

Charles, a recently retired cardiologist of 53 years, speaks with David Rintell, Head of Patient Advocacy at BridgeBio, and Mandy Rohrig, Director of Patient Advocacy at BridgeBio Gene Therapy, about how his unexpected early diagnosis of ATTR-CM likely impacted the trajectory of his disease. Dr. Jonathan Fox, President and Chief Medical Officer of cardiorenal programs at BridgeBio, explains how ATTR affects the heart and peripheral nervous system, and the importance of early diagnosis.   For years, Charles suffered from numbness and tingling in both wrists and hands. Eventually, when the pain became so severe that operating a mouse for 10 to 15 minutes was difficult, he was referred to a hand surgeon who recommended carpal tunnel surgery. Preparing for the surgery, Charles recalled reading a medical journal article that indicated 10% of people who underwent carpel tunnel surgery had positive tissue biopsy indicative of ATTR-CM. He requested that his surgeon perform a biopsy and shortly thereafter received his diagnosis. The transition from doctor to patient was not easy for Charles. However, he feels fortunate to be a cardiologist, to have read and remembered the article, requested a biopsy, and received the diagnosis more quickly than many others who live with ATTR. “I have three passions: running, traveling, and teaching," Charles shared. The early diagnosis has allowed him to continue to live a full, active life, running nearly daily as he has for the past 45 years. Charles, now 86, continues to serve others, spending his retirement teaching and mentoring health care providers around the country about ATTR and volunteering for amyloidosis advocacy organizations.

Darshan H. Brahmbhatt, Podcast Editor of JACC: Advances, discusses a recently published original research paper on DPD quantification correlates with extracellular volume and disease severity in wild-type transthyretin cardiac amyloidosis.

Join host Jane McEachan as she welcomes Nicolas Bigorre from the Centre de la Main in France and Carlos Heras-Palou from the Pulvertaft Centre in the UK. Together, they dive into the topic of Transthyretin Amyloidosis (ATTR) and its link to Carpal Tunnel Syndrome. Discover the latest insights from these experts on how this condition presents, its implications for patients, and what clinicians should be aware of in diagnosis and management. Paper discussed - Prevalence of transthyretin amyloidosis in patients undergoing carpal tunnel surgery: a prospective cohort study and risk factor analysis

JACC: Heart Failure Social Media Editor Giorgia Benzoni, MD, discusses a recently published Leading Edge Commentary comparing the pathophysiological differences between ATTR and AL cardiac amyloidosis and implications for therapy.

Cardiac Amyloidosis: No Longer Rare and Untreatable!      Guest: Omar F. Abou Ezzeddine, M.D., M.S. Hosts: Malcolm R. Bell, M.D.   Transthyretin amyloid cardiomyopathy (ATTR-CM), once considered rare, is more prevalent than previously thought. Diagnosing ATTR-CM is particularly important because there are now highly effective, specific therapies for ATTR-CM. In this podcast, we will provide a contemporary review of the diagnostic and therapeutic approach to patients with ATTR-CM in the current era.   Topics Discussed: When to suspect the disease & who to screen for ATTR-CM? How to diagnose and prognosticate ATTR-CM in the current era? Provide an overview of current and emerging therapies for managing ATTR-CM.   Connect with Mayo Clinic's Cardiovascular Continuing Medical Education online at https://cveducation.mayo.edu or on Twitter @MayoClinicCV and @MayoCVservices. LinkedIn: Mayo Clinic Cardiovascular Services Cardiovascular Education App: The Mayo Clinic Cardiovascular CME App is an innovative educational platform that features cardiology-focused continuing medical education wherever and whenever you need it. Use this app to access other free content and browse upcoming courses. Download it for free in Apple or Google stores today! No CME credit offered for this episode. Podcast episode transcript found here.

Ron Witteles, MD, and and Andrew Nguyen, MD, discuss the study design and findings of HELIOS-B, and clinical impact of vutrisiran in transthyretin amyloid cardiomyopathy.

6th ESC 2024: Vutrisiran

Editor-in-Chief Eric Rubin and Deputy Editor Jane Leopold discuss research that was presented at the 2024 European Society of Cardiology annual meeting. Visit NEJM.org to read the latest research.

Interview with Luis R. Lopes, PhD, author of Prevalence, Cardiac Phenotype, and Outcomes of Transthyretin Variants in the UK Biobank Population, and Senthil Selvaraj, MD, MS, MA, author of Genotype- vs Phenotype-Guided Approaches to Improve ATTR Detection. Hosted by Sharlene M. Day, MD. Related Content: Prevalence, Cardiac Phenotype, and Outcomes of Transthyretin Variants in the UK Biobank Population Genotype- vs Phenotype-Guided Approaches to Improve ATTR Detection

Interview with Luis R. Lopes, PhD, author of Prevalence, Cardiac Phenotype, and Outcomes of Transthyretin Variants in the UK Biobank Population, and Senthil Selvaraj, MD, MS, MA, author of Genotype- vs Phenotype-Guided Approaches to Improve ATTR Detection. Hosted by Sharlene M. Day, MD. Related Content: Prevalence, Cardiac Phenotype, and Outcomes of Transthyretin Variants in the UK Biobank Population Genotype- vs Phenotype-Guided Approaches to Improve ATTR Detection

Darshan H. Brahmbhatt, Podcast Editor of JACC: Advances discusses a recently published original research paper on Age- and Sex-Related Differences in Patients with Wild-Type Transthyretin Amyloidosis

In this podcast, Dr. Nowell Fine discusses a study on atrial fibrillation as a prognostic factor in patients with transthyretin amyloidosis cardiomyopathy, highlighting its high prevalence but limited prognostic significance. The research, part of the TTR ACT trial, underscores the need for ongoing investigation into optimal management strategies for atrial fibrillation in this complex patient population.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME information, and to apply for credit, please visit us at PeerView.com/ZHC865. CME credit will be available until July 15, 2025.TTRemendous Advances in Transthyretin Amyloidosis Treatment: What Neurologists Need to Know In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an independent educational grant from AstraZeneca LP.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME information, and to apply for credit, please visit us at PeerView.com/ZHC865. CME credit will be available until July 15, 2025.TTRemendous Advances in Transthyretin Amyloidosis Treatment: What Neurologists Need to Know In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an independent educational grant from AstraZeneca LP.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME information, and to apply for credit, please visit us at PeerView.com/ZHC865. CME credit will be available until July 15, 2025.TTRemendous Advances in Transthyretin Amyloidosis Treatment: What Neurologists Need to Know In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an independent educational grant from AstraZeneca LP.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME information, and to apply for credit, please visit us at PeerView.com/ZHC865. CME credit will be available until July 15, 2025.TTRemendous Advances in Transthyretin Amyloidosis Treatment: What Neurologists Need to Know In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an independent educational grant from AstraZeneca LP.Disclosure information is available at the beginning of the video presentation.

Sean joins David Rintell, Head of Patient Advocacy at BridgeBio, and Mandy Rohrig, Director of Patient Advocacy at BridgeBio Gene Therapy to share his journey with ATTR. In this episode, Sean describes his initial symptoms, which included carpal tunnel syndrome and numbness in his foot and ankle, the misdiagnosis he experienced, and his eventual diagnosis at the Cleveland Clinic in Abu Dhabi. While the diagnosis was a relief it was also difficult to accept and took an emotional toll on him and those around him. Sean has found this to be a common experience of many diagnosed with ATTR. Since Sean's form of ATTR is hereditary, various members of his family have also been tested. Sean also highlights the positive changes in his life, including meeting his wife, Robin, discovering a talent for drawing, and becoming a public speaker about ATTR. Jonathan Fox, President and Chief Medical Officer of cardiorenal programs at BridgeBio, joins us again to give a medical introduction to ATTR. On this episode, Jonathan highlights the differences of the ATTR T80 variant. Previously, we learned that ATTR amyloidosis is caused by the dissociation of a protein called transthyretin, or TTR, that changes its shape and forms into fibrous clumps. These clumps of misshapen protein are deposited into various organs and peripheral nerves, including the heart, which can cause them to function abnormally. Jonathan explains the possible origin of the T80 variant and how the T80 variant symptoms can differ from ATTR-CM.   To learn more about living with amyloidosis visit Mackenzie's Mission, www.mm713.org

In less than 15 minutes, Medmastery's Cardiology Digest will give you the low-down on some of the most compelling studies in cardiology that clinicians with an interest in cardiovascular health need to know about. STUDY #1: We kick things off by exploring exactly where the CHA2DS2-VASc score fits into anticoagulation decisions in patients with silent atrial fibrillation. Building on the main findings from the ARTESiA and NOAH-AFNET 6 trials, this study sparks a thought-provoking discussion on the future of risk stratification. Tune in to hear insights that could shape your clinical practice.  Lopes, RD, Granger, CB, Wojdyla, DM, et al. 2024. Apixaban versus aspirin according to CHA2DS2-VASc score in subclinical atrial fibrillation: Insights from ARTESiA. J Am Coll Cardiol. In Press, Journal Pre-proof. (https://doi.org/10.1016/j.jacc.2024.05.002) STUDY #2: Next, we break down misconceptions surrounding race and treatment efficacy in heart failure with reduced ejection fraction. This study shines a light on the impacts of renin-angiotensin system inhibition across different racial groups. See how these findings challenge the outdated genetic constructs of race, and what they mean for your approach to patient care. Shen, L, Lee, MM, Jhund, PS, et al. 2024. Revisiting race and the benefit of RAS blockade in heart failure: A meta-analysis of randomized clinical trials. JAMA. 24: 2094–2104. (https://doi.org/10.1001/jama.2024.6774) STUDY #3: Finally, we turn our focus to the V142I transthyretin gene variant, to evaluate its impacts on cardiovascular health within the U.S. Black population. This research not only highlights the need for targeted genetic screening but also raises important questions about the accessibility of costly treatments for transthyretin amyloidosis. Selvaraj, S, Claggett, B, Shah, SH,  et al. 2024. Cardiovascular burden of the V142I transthyretin variant. JAMA. 21: 1824–1833. (https://doi.org/10.1001/jama.2024.4467) Maurer, MS, Miller, EJ, Ruberg, FL, et al. 2024. Addressing health disparities—The case for variant transthyretin cardiac amyloidosis grows stronger. JAMA. 21: 1809–1811. (https://doi.org/10.1001/jama.2024.2868) Yancy, CW. 2024. Heart failure in African American individuals, Version 2.0. JJAMA. 21: 1807–1808. (https://doi.org/10.1001/jama.2024.5217) Don't miss out on this rich discussion that promises to enhance your understanding and expertise!  Learn more with these courses: Medical Treatment of Heart Failure (2 CME) Atrial Fibrillation Management Essentials (1 CME) Get a Basic or Pro account, or, get a Trial account. Show notes: Visit us at  https://www.medmastery.com/podcasts/cardiology-podcast.

Audio Commentary by Dr. Valentin Fuster, Emeritus Editor in Chief

Commentary by Trejeeve Martyn and Julia Simkowski

Commentary by Dr. Valentin Fuster

What is the natural history and cardiovascular burden of the V142I transthyretin variant among US Black individuals who carry this variant? Senthil Selvaraj, MD, MS, MA, from Duke University, and Scott D. Solomon, MD, from Brigham and Women's Hospital, discuss this and more with JAMA Executive Editor Gregory Curfman, MD. Related Content: Cardiovascular Burden of the V142I Transthyretin Variant Addressing Health Disparities—The Case for Variant Transthyretin Cardiac Amyloidosis Grows Stronger Heart Failure in African American Individuals, Version 2.0 Cardiac Amyloidosis Due to Transthyretin Protein

In part two, Eric continues talking about his experience living with Transthyretin Amyloidosis (ATTR) with David Rintell, Head of Patient Advocacy at BridgeBio, and Mandy Rohrig, Director of Patient Advocacy at BridgeBio Gene Therapy. Eric recalls the surprise he experienced when a routine doctor's visit led to him, within hours, to undergoing a heart transplant. Though the surgery was successful, Eric describes his complex recovery from the transplant. Age, old sports injuries, and lingering ATTR symptoms all contributed to a year-long recovery process, which included a two-week stay in the hospital, followed by an acute rehabilitation facility, a few weeks in a hotel, and several more months of recovery at home. Eric ends the conversation by stressing the importance of community – strong connections with other people were not only crucial to his recovery, but also opened doors for mentorship, activism, and his current involvement with the Northern California Amyloidosis Support Group.

Commentary by Bonnie Ky

Eric joins David Rintell, Head of Patient Advocacy at BridgeBio and Mandy Rohrig, Director of Patient Advocacy at BridgeBio Gene Therapyin a two-part conversation to talk about his experience of living with Transthyretin Amyloidosis (ATTR). Eric was an extremely active person who enjoyed sports, riding horses and working on his 20-acre property when he began to have issues which he now attributes to ATTR. Eric's diagnostic journey took 14 years and as the disease progressed, he experienced two carpal tunnel surgeries, and several other cardiac procedures. In fact, by the time he was diagnosed, Eric could not walk the length of his home (60 feet) without getting out of breath. Four years after his diagnosis he received a heart transplant. Despite the difficulties, Eric highlights the positives of this diagnosis and how living with ATTR and engaging with the ATTR community has taught him to be intellectually curious, empathetic, grateful for the care he has received and happy to be alive.  Jonathan Fox, President and Chief Medical Officer of cardiorenal programs at BridgeBio. Jonathan explains the causes of ATTR and what happens to people living with it. ATTR amyloidosis is caused by the dissociation of a protein called transthyretin, or TTR, that changes its shape and forms into fibrous clumps. These clumps of misshapen protein are deposited into various organs and peripheral nerves, including the heart, which can cause them to function abnormally.

Do you know how to interpret the results of recent phase 3 clinical trials in patients with transthyretin amyloid cardiomyopathy (ATTR-CM)? Credit available for this activity expires: 3/22/25 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/1000444?ecd=bdc_podcast_libsyn_mscpedu

Systemic amyloidosis from transthyretin (ATTR) protein is increasingly recognized as an important cause of heart failure in older people. JAMA Deputy Editor Mary McGrae McDermott, MD, discusses the diagnosis and treatment of ATTR protein cardiomyopathy with Frederick L. Ruberg, MD, of the Boston University Chobanian & Avedisian School of Medicine. Related Content: Cardiac Amyloidosis Due to Transthyretin Protein

Laura Obici, MD - Taking Action to Improve the Patient Journey With Transthyretin Amyloidosis (ATTR): Shared Perspectives From Patients and Providers

Laura Obici, MD - Taking Action to Improve the Patient Journey With Transthyretin Amyloidosis (ATTR): Shared Perspectives From Patients and Providers

Laura Obici, MD - Taking Action to Improve the Patient Journey With Transthyretin Amyloidosis (ATTR): Shared Perspectives From Patients and Providers

Laura Obici, MD - Taking Action to Improve the Patient Journey With Transthyretin Amyloidosis (ATTR): Shared Perspectives From Patients and Providers

Laura Obici, MD - Taking Action to Improve the Patient Journey With Transthyretin Amyloidosis (ATTR): Shared Perspectives From Patients and Providers

Laura Obici, MD - Taking Action to Improve the Patient Journey With Transthyretin Amyloidosis (ATTR): Shared Perspectives From Patients and Providers

Interview with Sanjiv J. Shah, MD, author of Effect of Tafamidis on Cardiac Function in Patients With Transthyretin Amyloid Cardiomyopathy: A Post Hoc Analysis of the ATTR-ACT Randomized Clinical Trial. Hosted by James E. Udelson, MD. Related Content: Effect of Tafamidis on Cardiac Function in Patients With Transthyretin Amyloid Cardiomyopathy

Interview with Sanjiv J. Shah, MD, author of Effect of Tafamidis on Cardiac Function in Patients With Transthyretin Amyloid Cardiomyopathy: A Post Hoc Analysis of the ATTR-ACT Randomized Clinical Trial. Hosted by James E. Udelson, MD. Related Content: Effect of Tafamidis on Cardiac Function in Patients With Transthyretin Amyloid Cardiomyopathy

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a type of systemic amyloidosis in which misfolded transthyretin protein is deposited in the myocardium. Early diagnosis of amyloidosis is necessary to prevent ATTR-CM and its dire consequences. It is increasingly recognized that early signs of amyloidosis may involve protein deposits in other parts of the body causing orthopedic, gastrointestinal, and neurologic pathologies among others. It is critical that clinicians from diverse specialties are knowledgeable regarding the early clues of amyloidosis to prevent the progression to ATTR-CM. This podcast will offer guidance on early identification of non-cardiac manifestations of amyloidosis from the perspective of the Gastrointestinal and Neurology clinical communities. 

Kelli Herrin, PharmD reviews the pathophysiology of transthyretin amyloidosis cardiomyopathy and provides updates on medication options.   For more pharmacy content, follow Mayo Clinic Pharmacy Residency Programs @MayoPharmRes. You can also connect with the Mayo Clinic's School of Continuous Professional Development online at https://ce.mayo.edu/ or on Twitter @MayoMedEd. 

Primary reference: Ticau S and Nioi P et al. (2021) Neurofilament Light Chain as a Biomarker of Hereditary Transthyretin-Mediated Amyloidosis. Neurology. 96(3):e412-e422. doi:10.1212/WNL.0000000000011090Information about the APOLLO clinical trial: “APOLLO: The Study of an Investigational Drug, Patisiran (ALN-TTR02), for the Treatment of Transthyretin (TTR)-Mediated Amyloidosis” Link to NCT01960348 at the US National Library of Medicine's Clinical Trials database https://clinicaltrials.gov/ct2/show/NCT01960348Epstein Barr Virus research presenting a stronger link between EBV and Multiple Sclerosis.Bjornevik K and Ascherio A et al. (2022) Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 375(6578):296-301. doi:10.1126/science.abj8222In case you were wondering, Proteomics in Proximity refers to the principle underlying Olink Proteomics assay technology called the Proximity Extension Assay (PEA), and more information about the assay and how it works can be found here.Would you like to subscribe to the podcast on your favorite player or app? You can do so here: Apple Podcasts: https://apple.co/3T0YbSm Spotify Podcasts: https://open.spotify.com/show/2sZ2wxOqI4b4vSngkajLs8?si=d957d55c8db046f7 Google Podcasts: https://podcasts.google.com/feed/aHR0cHM6Ly9mZWVkcy50cmFuc2lzdG9yLmZtL3Byb3Rlb21pY3MtaW4tcHJveGltaXR5 Amazon Music: https://music.amazon.com/podcasts/d97ace94-f02b-4b37-9532-799548ef2840 Podcast Addict: https://podcastaddict.com/podcast/4098296 Deezer: https://www.deezer.com/show/5178787 Player FM: https://player.fm/series/series-3396598

This week, please author Gemma Figtree and Associate Editor Nicholas Mills as they discuss the Frontiers article "Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease Drug Development." Dr. Greg Hundley: Welcome listeners to this November 29th, 2022 issue of Circulation On the Run. I am one of your hosts, Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Peder Myhre: I am Dr. Peder Myhre from Akershus University Hospital and University of Oslo in Norway. Dr. Greg Hundley: Well, Peder this week's feature discussion very interesting. It is a state of the art review and it involves noninvasive plaque imaging and really how we might assess plaques to evaluate whether coronary artery disease is accelerating. Very important information by a large group of clinician scientists that will develop programs that, maybe, can be used in therapeutic drug development. Dr. Peder Myhre: That's so interesting, Greg. Dr. Greg Hundley: Right. A great group of individuals all put together, but before we get to that interesting feature discussion how about we grab a cup of coffee and start with some of the other articles in the issue? How about this week I go first? Dr. Peder Myhre: Go ahead Greg. Dr. Greg Hundley: Peder, these authors led by Marianna Fontana from University College London Medical School sought to characterize changes in the clinical phenotype of 1,967 patients with a diagnosis of transthyretin cardiac amyloidosis over the last 20 years enrolled and participating in the National Amyloidosis Center from 2002 to 2021. Dr. Peder Myhre: Oh yes, Greg, please. This cardiac amyloidosis we have to learn more about it. Please, tell me what did they find. Dr. Greg Hundley: Right, Peder. First, there's been a substantial increase in the number of patients diagnosed with transthyretin amyloid in recent years. This is associated with greater proportions of patients referred following cardiovascular magnetic resonance imaging and bone scintigraphy scans. Second, transthyretin amyloid patients are often now being diagnosed much earlier in their disease process, as evidenced by a shorter duration of symptoms prior to diagnosis, milder stages of disease, and more favorable structural and functional echocardiographic changes at the time of diagnosis. Then, finally, mortality in these transthyretin amyloids patients has improved substantially in recent times aside from any potential benefits from disease modifying treatment or participation in clinical trials. Dr. Peder Myhre: Wow. Greg, over the course of 20 years we have seen some differences in the diagnosis or cardiac ATTR amyloidosis, so what would you say are the take home messages from this paper, Greg? Dr. Greg Hundley: Right, Peder. Transthyretin amyloid is now often diagnosed earlier in the disease process with improved prognosis. I think, more data needed to guide decisions on in whom and when to initiate treatment and then which treatments should be used at each stage of the disease. Peder, along with this article there's an excellent editorial by Doctors Patel and Maurer entitled “The Future for Patients with Transthyretin Cardiac Amyloid is, It's Looking Brighter.” Dr. Peder Myhre: Okay. Greg, I'm going to continue in the field of clinical research and this paper actually describes a new ablation technique for ventricular tachycardia. Isn't that exciting? Dr. Greg Hundley: Absolutely. Dr. Peder Myhre: The paper comes to us from corresponding author Miguel Valderrabano from Houston Methodist Hospital in Texas and is entitled “Substrate Ablation by Multi-vein, Multi-balloon Coronary Venous Ethanol for Refractory Ventricular Tachycardia and Structural Heart Disease.” Ablation of ventricular tachycardia, VT, in the setting of structural heart disease often requires extensive substrate elimination, which is not always achievable by endocardial radiofrequency ablation and epicardial ablation is not always feasible. The left ventricle venous circulation allows vascular access to reach intramural substrates of VT in the context of myocardial infarction or non-ischemic scar, where radiofrequency ablation has limited success. Greg, in this study the authors enroll patients with ablation refractory VT and used phonography and epicardial mapping to perform a double balloon venous ethanol ablation. That is, by blocking flow with one balloon and injecting ethnol via this second balloon. Dr. Greg Hundley: Peder, what a beautiful description and very interesting strategy to address this situation. What did they find? Dr. Peder Myhre: Greg, after the venous ethanol ablation vein maps and epicardial maps showed elimination of abnormal electrograms of the VT substrate an intracardiac echocardiography demonstrated increased intramural echodensity at the target lesions of the 3D maps and at one year of follow up VT recurrence occurred in seven patients, which translates into a success rate of 84%. The authors conclude that multi-balloon multi-vein intramural ablation by venous ethanol ablation can provide effective substrate ablation in patients with ablation refractory VT in the setting of structural heart disease over a broad range of left ventricular locations. Dr. Greg Hundley: Very nice, Peder. What a beautiful description. Excellent. Well, this next paper Peder comes to us from the world of preclinical science and these authors led by Professor Christine Sideman from the Harvard Medical School evaluated alpha-kinase 3. Now, alpha-kinase three is a muscle specific protein in which loss of function variants cause cardiomyopathy with distinctive clinical manifestations in both children and adults. At presence the muscular functions of alpha-kinase 3 remain poorly understood, so to address this dilemma these investigators explored the punitive kinase activity of alpha-kinase 3 and the consequences of damaging variants using isogenic human induced pluripotent stem cell derived cardiomyocytes. Mice and human patient tissues. Dr. Peder Myhre: Okay, Greg. This sounds like impressive basic science work, so what did the authors find. Dr. Greg Hundley: Right, Peder. Damaging variance in alpha-kinase 3 encoding an abundant muscle specific protein caused both neonatal and adult onset cardiomyopathies and led to both ventricular dilation and hypertrophy. Now, although alpha-kinase three contain an alpha kinase domain the team showed that it lacks catalytic activity and is really a pseudo kinase. Then finally, Peder, alpha-kinase 3 localizes to both the nuclear envelope of cardiomyocytes and the M-band of the sarcomere where it regulates the expression and localization of myomesins, myomesin 1 and myomesin 2, and additional M-band proteins important for sarcomere protein turnover. Dr. Peder Myhre: That is a beautiful summary, Greg. Since you did so well at summarizing this difficult topic, I'm not going to ask you what a clinical implications, but rather to take home messages here. Dr. Greg Hundley: Very nice. Glad you asked Peder. First, alpha-kinase 3 cardiomyopathy may cause impaired contractility and ventricular dilation due to miss localization and dysregulation of myomesin proteins which are critical for force buffering in cardiomyocytes. Next, alpha-kinase 3 cardiomyopathy may cause hypertrophy due to dysregulation of key M-band proteins, which are important for sarcomere protein turnover. Then finally, therapeutic strategies to restore cardiomyocyte force buffering functions and sarcomere protein turnover may ameliorate disease phenotypes in patients with alpha-kinase three cardiomyopathy. Dr. Peder Myhre: Thank you Greg. The next paper is also from the field of preclinical science and it is about the Hippo-YAP signaling pathway which maintains sinal atrial node homeostasis. It comes to us from the corresponding author Jun Wang from the University of Texas Health Science Center at Houston. Greg, this paper is not about hippos, but it is about the Hippo signaling pathway, which is known to control organ size and growth in animals and humans. These authors sought to investigate this pathway in relation to the sinal atrial node, i.e. The sinus node. As you know Greg, the sinal atrial node functions as the pacemaker of the heart initiating rhythmic heartbeats. Despite its importance the sinal atrial node is one of the most poorly understood cardiac entities, because of its small size and complex composition and function. To uncover the function of Hippo signaling in sinal atrial node the authors use knockout mice and a series of physiological and molecular experiments including telemetry, electrocardiogram recording, echochoreography, calcium imaging, immunostaining, ANA scope, quantitative real time PCR, and western blotting. Dr. Greg Hundley: Wow, Peder, that sounds like quite an extensive series of experiments. What did they find? Dr. Peder Myhre: Deletion of essential Hippo kinases caused increased fibroblast proliferation and fibrosis in the sinal atrial node. They also found evidence suggesting that Hippo signaling regulates calcium hemostasis in pacemaker cells and that may be partially mediated by the regulation of genes and coding key calcium handling proteins such as RYR2. Finally, the demonstrated that deletion of Hippo effectors in the sin atrial node can rescue the defect previously described. Greg, the take home messages is that Hippo signaling was found to be an important regulator of the sinal atrial node homeostasis and that this provide insights applicable to the treatment of patients with sinus node dysfunction. Dr. Greg Hundley: Ah, beautifully done Peder. Beautifully done. We've got some other articles in this issue. Let me tell you about a Research Letter. It's from Professor Nazer entitled “Targeted Screening for Transthyretin Amyloid Cardiomyopathy in Patients with Atrial Fibrillation.” Then Tracy Hampton has a whole series of cardiology news highlighting first that primary cilia are critical for exercise induced muscle hypertrophy. This is from the proceedings of the National Academy of Sciences. Next, there's a discussion of whole body reperfusion techniques to restore function in pig organs after death, that comes to us from nature. Then lastly, there's a final article scientists identify diverse pathogenic gene variants that lead to heart failure from the journal science. Dr. Peder Myhre: Thank you, Greg. Finally, there is one Perspective piece by Dr. Rajiv Agarwal from Indiana University School of Medicine entitled “Hydrochlorothiazide versus Chlorthalidone: What is the difference?” Now, let's move on to the feature discussion that I know you are very excited about, Greg, to learn more about the non-invasive plaque imaging in our frontiers of medicine.   Dr. Greg Hundley: You bet. Well listeners, welcome to this feature discussion today on November 29th and we have with us Dr. Gemma Figtree from Sydney, Australia and our own associate editor, Dr. Nick Mills from Edinburgh, Scotland. Welcome to you both. Listeners, this is a really interesting feature discussion. It's one of our Frontiers articles that combines where we are in the past, but also where we want to move in the future and a very nice comprehensive review with many articles. Gemma, can you describe for us the genesis really of this article and what you've been working on? Dr. Gemma Figtree: Thanks so much, Greg. Look, I think it's very exciting times at the moment and it's a really important time for all of our community to actually get together in this space. We are driven by trying to make a more efficient process for drug discovery and translation to occur and to basically move into humans in the space of coronary artery disease. We've actually known, obviously, for a long time that the underlying process driving heart attack, but we've not been able to image and treat the actual underlying disease. What this article focuses on is how we actually merge top current technology with policy and approval of drugs. We are very excited about the team of over 20 different institutes around the world trying to work on the best measures of corona artery disease as the disease itself. Dr. Greg Hundley: Very nice. Now, help us understand different techniques and why is this a frontier? Dr. Gemma Figtree: Look, I think it's a mixture of the fact that, obviously, we're getting great advances in noninvasive imaging techniques that allow us to actually measure plaque burden, but also plaque characteristics. In the case of drug translation this is an absolutely fundamental piece. You can transform a clinical trial where you can look at the underlying pathology and be able to enrich trials or be able to look at the effect of trials of a new drug in humans. It's really important to acknowledge the fact that humans are really the only animal on the planet that get corona artery disease itself. To be able to translate some of the exciting new drugs that target the plaque itself and work synergistically with some of our agents on cholesterol, and blood pressure, et cetera, we really need to have these measures of coronary artery disease itself. It's a combination of the technology, but also how we apply it to a clinical trial and then how do we work with our regulatory authorities and policy advisors around getting this into humans. We really aiming to try to accelerate the development of drugs that can try to tackle our greatest burden of cardiovascular disease around the world. Dr. Greg Hundley: I'm hearing cardiovascular disease, I also heard in their imaging and lots of different modalities, and then I heard regulatory bodies. Are you thinking maybe we need standards? Dr. Gemma Figtree: That's exactly right. I think, importantly, whilst there's a lot of exciting technology and a lot of us are pursuing potentially different avenues of this we also need to be able to coordinate and develop a simple and harmonized approach that's able to be applied across the world in an equitable fashion. Whilst we, obviously, have developing exciting new toys we have to make sure that a measure that we want to work with regulatory authorities is able to be applied in all of our countries around the world to make sure that the drug development is applied in an equitable fashion. Dr. Greg Hundley: Very nice. Well listeners, next we're going to turn to our associate editor, Dr. Nick Mills. Nick, you evaluate many manuscripts. What attracted you to this particular paper? Also, help us put it in the context of why you think it's a new frontier that is emerging or needs to emerge in cardiovascular disease. Dr. Nick Mills: Yeah, thanks Greg. Three things, the expertise of this group, the focus and novelty of the topic, and the fact that it's a really timely issue Gemma just outlined. Gemma a phenomenal job bringing together people from all over the world to tackle this area that includes imaging expertise, drug development expertise, industry that gives it a very balanced and diverse range of views and marks it out from other reviews that focus on particular imaging modality. Novelty's really important, but timeliness as well. We've seen in the last five years major breakthroughs in the treatment of diabetes and heart failure. But, drug development of coronary heart disease is stalling. I cannot remember the last time I went to a really exciting late breaking trial on a new development for coronary heart disease that has changed the outcomes for patients. We do need to rethink. Gemma's absolutely right, that requires us to work with regulators to stimulate industry involvement in drug discovery, and delivery, and testing. This is occurring at a time where we've got more fabulous imaging modalities then we've ever had before. Critically, they're noninvasive. They're easy for patients, they're easy for serial testing, and that really opens up many opportunities. It's the fact that it's timely, novel, great expertise, and also really exciting area for cardio of medicine. Dr. Greg Hundley: Very nice. Well listeners, we're going to go back to Gemma. Gemma, what do you think are some of the next research studies that we need to perform to support what we're trying to indicate today in this Frontiers article? Dr. Gemma Figtree: Yeah. Thanks very much, Greg. I think, ultimately, the features that need to be taken into consideration for a surrogate endpoint to be approved by our regulatory authorities need to be considered. There are many drug companies, but also individual investigators with ideas of drugs to take forward. What we need to do is make sure for all those studies that we're actually working together and ideally having a harmonized endpoint for use there. I think, working early with regulatory authorities is going to be key. I think, if you actually, within the tables that are presented in the paper we demonstrate very clearly that these measures of plaque, particularly, the CT coronary angiography measures of low attenuation plaque are pretty ready for consideration by regulatory authorities. I think, agents that we already know work to reduce mortality, such as statins, we know that they actually have direct effects on plaque both from a pathophysiological perspective, but also from these imaging studies. We know that that change in the plaque characteristics and volume predict the outcomes. In a sense, we've got a fabulous array of data already. In fact, new agents that have come through have also demonstrated effects on these measures. I think, by bringing all of this together in this article we're already in a position to work with regulatory authorities to see what is needed next. I think, listening to that's going to be very important. I do think that the next steps are really going to be working with effectively, I guess, our colleagues to make sure that we don't continue to rapidly advance the measures whilst losing the opportunity to work with regulatory authorities. In answer your question about the research side of things, I think, as we gather more and more information about this we have to make sure that phase two studies are then linked and we can retrospectively see how they predict the outcomes in phase three studies, but I firmly believe that we're in a position that over the next couple of years we should be able to do harmonized approaches at phase two studies and then as a whole community be able to look at how that predicts outcome and work with our regulatory authorities to get more confidence in these endpoints as key. This is all driven by my clinical observations and interest in people who look up and say, "Why me" when they're having a heart attack? In our community where we're getting very good primary prevention we see up to 25% of our heart attack patients having plaque events and catastrophic heart attacks without those traditional risk factors that would've worn them. Part of this is also opening up avenues for driving new diagnostic tools that can pick up the disease itself. Picking up... Treating coronary disease as the disease and using that for diagnostic and therapeutic purposes, I think, is a great opportunity to tackle this great burden that we're currently not winning with. Dr. Greg Hundley: With the group that you had assembled were there any primary suggestions on how to unite some of these efforts on a global scale? I really liked, very early in our conversation today, you mentioned that and I wondered what this collective you assembled may have suggested. Dr. Gemma Figtree: Yeah. Look, I think at the moment it is a collection of experts. I haven't quite figured out the name for such a thing, but we are also working with some of the leading organizations now to try to also make sure we get their auspicing of the concepts and how to best do that. I think, by not coming out of one particular organization and evolving from the members itself, and in particular, having industry and regulatory authorities involve and drug discovery experts right from the beginning has been fantastic. Also, making sure that we have that pragmatic approach and that consideration of equitable access. Particularly, making sure that any phase two trial can be done or enrichment for phase three trial can be applied right around the globe and make sure we get diversity of patients enrolled in these studies. Dr. Greg Hundley: Very nice. Coming back to you, Nick, any additional thoughts to build on Gemma's comments here? Dr. Nick Mills: Well, to say as someone who's worked in the field of cardiac biomarkers for many years and felt that we could tackle this with the regulators and drug delivery, but I've seen inflammatory biomarkers, lipoproteins come and go without changing. I think, it's just a really exciting opportunity that we now have the ability to phenotype an image, coronary artery disease noninvasively, but a highly specific surrogate endpoint that we've never had before. It's why I'm starting to do research into DT. Dr. Greg Hundley: Very nice. Well listeners, we want to thank Dr. Gemma Figtree from Sydney, Australia and our own associate editor, Dr. Nick Mills for bringing us this really provocative Frontiers article highlighting a new strategy. Bringing together regulators, leading researchers, and industry to advance new methodologies and trying to tackle globally how we might address atherosclerosis. Well, on behalf of Peder, Carolyn, and myself we want to wish you a great week and we will catch you next week on The Run. This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Commentary by Dr. Dan Lenihan

Neste terceiro e último episódio sobre PAF da PEBMED em parceria com a Pfizer, Marcelo Gobbo e Viviane Carvalho falarão sobre tratamento e modalidades terapêuticas. Por ser uma doença grave e progressiva, estabelecer o estágio de Polineuropatia Amiloidótica Familiar, PAF, em que o paciente se encontra é fundamental porque alguns tratamentos, por exemplo, são indicados em alguns estágios específicos. Referências bibliográficas: 1-Adams D, et al. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol. 2019 Jul;15(7):387-404. doi: 10.1038/s41582-019-0210-4. Epub 2019 Jun 17. PMID: 31209302. 2- Vieira M, Saraiva MJ. Transthyretin: a multifaceted protein. Biomol Concepts. 2014 Mar;5(1):45-54. doi: 10.1515/bmc-2013-0038. PMID: 25372741. 3-Coutinho P, Martins da Silva A, Lopas LJ (1980) Forty years of experience with type 1 amyloid neuropathy. Review of 483 cases. In: Amyloid and amyloidosis. Excerpta Medica, Amsterdam, pp 88–98 4- Ando Y, et al. Guideline of transthyretin- related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31 5- Dyck PJB, González-Duarte A, Obici L, Polydefkis M, Wiesman JF, Antonino I, Litchy WJ, Dyck PJ. Development of measures of polyneuropathy impairment in hATTR amyloidosis: From NIS to mNIS + 7. J Neurol Sci. 2019 Oct 15;405:116424. doi: 10.1016/j.jns.2019.116424. Epub 2019 Aug 8. PMID: 31445300. 6- Adams, David et al. “First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy.” Current opinion in neurology vol. 29 Suppl 1,Suppl 1 (2016): S14-26. doi:10.1097/WCO.0000000000000289 7- Ministério da Saúde (Brasil). Comissão Nacional de Incorporação de Tecnologias no SUS (CONITEC). Relatório de recomendação: Tafamidis meglumina no tratamento da polineuropatia amiloidótica familiar relacionada à proteína transtirretina. Brasília: Ministério da Saúde; 2018. 43 p 8- Suhr O. Impact of liver transplantation on familial amyloidotic polyneuropathy (FAP) patients' symptoms and complications. Amyloid. 2003;10(Suppl. 1):77–83 9-Bula do Produto: https://www.pfizer.com.br/sit es/default/files/inline- files/Vyndaqel_Profissional_ de_Saude_19.pd 10-Ministério da Saúde (Brasil). Protocolos Clínicos e Diretrizes Terapêuticas - PCDT. Disponível em: https://www.gov.br/saude/pt-br/assuntos/protocolos-clinicos-e-diretrizes-terapeuticas-pcdt/protocolos-clinicos-e-diretrizes-terapeuticas-pcdt

Neste episódio especial da PEBMED em parceria com a Pfizer, Marcelo Gobbo, médico de comunidade e família e editor médico do Portal recebe a neurologista Viviane Carvalho para falar sobre PAF, a Polineuropatia Amiloidótica Familiar, uma condição rara que pode ter sua trajetória modificada quando identificada precocemente e adequadamente tratada. Referências Bibliográficas: 1- Picken MM. The Pathology of Amyloidosis in Classification: A Review. Acta Haematol. 2020;143(4):322-334. doi: 10.1159/000506696. Epub 2020 May 11. PMID: 32392555. 2- Adams D, Koike H, Slama M, Coelho T. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol. 2019 Jul;15(7):387-404. doi: 10.1038/s41582-019-0210-4. Epub 2019 Jun 17. PMID: 31209302. 3- Guevara C, Barrientos N, Flores A, Idiáquez J. Polineuropatia amiloidótica familiar tipo I. Rev Méd Chile. 2003;131:1179-82. 4- Centenário do nascimento de Corino de Andrade. Sinapse, publicação da Sociedade Portuguesa de Neurologia, Suplemento 1, Volume 6, Nº1, Maio de 2006. 5- Andrade, C. A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain. 1952 Sep;75(3):408-27. doi: 10.1093/brain/75.3.408. PMID: 12978172.) 6- Saporta, M. A. C., C Zaros, M W Cruz, C André, M Misrahi, et al. "Penetrance estimation of TTR familial amyloid polyneuropathy (type I) in Brazilian families." European journal of neurology 16.3 (2009): 337-341. 7- Vieira M, Saraiva MJ. Transthyretin: a multifaceted protein. Biomol Concepts. 2014 Mar;5(1):45-54. doi: 10.1515/bmc-2013-0038. PMID: 25372741. 8- Galant NJ, Westermark P, Higaki JN, Chakrabartty Al. Transthyretin amyloidosis: an under-recognized neuropathy and cardiomyopathy. Clin Sci. 2017 ;131(5):395-409 9-Simões M. V., Fernandes F, Marcondes-Braga F, Scheinberg P, Correia E, et al. Posicionamento sobre Diagnóstico e Tratamento da Amiloidose Cardíaca (2021). Arquivos Brasileiros de Cardiologia, 117, 561-598. 10- Bonaiti B, Olson M, Hellman U, Surh O, Bonaiti-Pellie C, et al. TTR familial amyloid polyneuropathy: does a mitochondrial polymorphism entirely explain the parent-of-origin difference in penetrance? Eur J Hum Genet. 2010;18(8):948- 52 11- Ando Y, Coelho T, Berk J, Cruz M, Ericzon B-G, et al. Guideline of transthyretin- related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31 12- Salvi F, Pastorelli F, Plasmati R, Bartolomei I, Dall'Osso D, et al. Genotypic and phenotypic correlation in an Italian population of hereditary amyloidosis TTR-related (HA-TTR): clinical and neurophysiological aids to diagnosis and some reflections on misdiagnosis. Amyloid. 2012;19 Suppl 1:58-60. 13-Gertz MA, Benson M, Dyck PJ, Grogan M, et al. Diagnosis, Prognosis, and Therapy of Transthyretin Amyloidosis. J Am Coll Cardiol. 2015 Dec 1;66(21):2451-2466. doi: 10.1016/j.jacc.2015.09.075. PMID: 26610878 14- Luiz F. Pinto, MD; and Marcus V. Pinto, MD, MS. The most common amyloidosis are both treatable; accurate diagnosis is paramount. Practical Neurology, July, 2021.

Transthyretin amyloid cardiomyopathy, or ATTR-CM, is a progressive and potentially fatal heart disease. It is often overlooked because physicians tend to consider more common causes of heart failure. Black, African American, and Afro-Caribbean communities are at the greatest risk for the genetic condition, but also face greater barriers to accessing care. We spoke to Pfizer Vice President and North America Medical Lead Younos Abdulsattar and Pfizer Chief Medical Officer of Rare Disease Sonal Bhatia, about ATTR-CM; its disproportionate impact on the Black, African American, and Afro-Caribbean communities; and steps Pfizer is taking to work with community organizations to raise awareness and improve care for people with the condition.

With Perry Elliott and Douglas Cannie, UCL Institute of Cardiovascular Science, London - UK Link to paper

Editor's Summary by Gregory Curfman, MD, Deputy Editor of JAMA, the Journal of the American Medical Association, for the April 12, 2022, issue.

Dr. Ricardo Taipa discusses his paper, "CNS Involvement in Hereditary Transthyretin Amyloidosis". Show references: https://n.neurology.org/content/97/24/1111

Commentary by Dr. Martha Grogan

Commentary by Dr. Sabahat Bokhari

Commentary by Dr. Nosheen Reza

Commentary by Dr. Olivier Florian Clerc

Dr. Alberto Espay talks with Prof. Julian Gillmore about CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. Show references: https://www.nejm.org/doi/full/10.1056/NEJMoa2107454  

Interview with Omar F. AbouEzzeddine, MDCM, MS and Margaret M. Redfield, MD, authors of Prevalence of Transthyretin Amyloid Cardiomyopathy in Heart Failure With Preserved Ejection Fraction

Interview with Omar F. AbouEzzeddine, MDCM, MS and Margaret M. Redfield, MD, authors of Prevalence of Transthyretin Amyloid Cardiomyopathy in Heart Failure With Preserved Ejection Fraction

Interview with Anne Tybjærg-Hansen, MD, DMSc, author of Association of Low Plasma Transthyretin Concentration With Risk of Heart Failure in the General Population

Interview with Anne Tybjærg-Hansen, MD, DMSc, author of Association of Low Plasma Transthyretin Concentration With Risk of Heart Failure in the General Population

Commentary by Dr. Ronald Witteles

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: I'm Greg Hundley, associate editor from the VCU Pauley Heart Center in Richmond, Virginia. Dr Carolyn Lam: Greg, amyloid cardiomyopathy is the rage. I cannot tell you the number of discussions I've had on the topic. Of course, it was tafamidis, the amazing results with that trial that really made us realize we need to pick this up. But have you ever thought about the cost effectiveness of tafamidis for amyloid cardiomyopathy? Well, guess what? We're going to have a whole feature discussion just about that. But first let's go to our summary, shall we? Dr Greg Hundley: You bet, Carolyn. Well, let me get started. I'm going to talk about regulation of cell cycle growth as well as division in regard to cardiac regeneration. My first paper comes from Dr Lior Zangi from the Mount Sinai School of Medicine. Well, Carolyn, have you ever wondered why the adult mammalian heart has limited regenerative capacity? Dr Carolyn Lam: All the time, Greg. Dr Greg Hundley: Well, of course you have. It's mostly due to postnatal cardiomyocyte cell cycle arrest. In this study the investigators evaluated the effect of pyruvate kinase muscle isozyme 2 and cardiomyocytes through models of loss, that is cardiomyocyte specific PKM2 deletion during cardiac development or gain using cardiomyocytes specific PKM to modified mRNA to evaluate PKM to function and regenerative effects post-acute or chronic MI in mice. Dr Carolyn Lam: Nicely described. What did they find, Greg? Dr Greg Hundley: What they found is that PKM2 is expressed in cardiomyocytes during development and immediately after birth, but not during adulthood. Using cardiomyocytes PKM to modified RNA, they found that cardiomyocyte targeted strategy following acute or chronic MI resulted in increased cardiomyocyte cell division, enhanced cardiac function, and improved long-term survival. They found that PKM2 regulates the cardiomyocyte cell cycle and reduces oxidative stress damage through anabolic pathways and beta-catenin. Dr Carolyn Lam: Cool, Greg. Man, this cardiac regeneration really, really is a hot area. Dr Greg Hundley: Carolyn, that is so insightful because these results really impact research toward unlocking pathways that could be involved in induction of myocyte cell division and regeneration in those sustaining MI or conditions like MI. Dr Carolyn Lam: Nice. Well, Greg, I'm going to change tones here and ask you, can we prevent atrial fibrillation with treatments for diabetes? Well, guess what? We have a paper next. It's from Dr Wiviott from the TIMI Study Group and his colleagues who really reason that since atrial fibrillation is associated with hypertension, obesity and heart failure in patients with diabetes and SGLT2 inhibitors have been shown to lower blood pressure, reduce weight, and reduce hospitalization for heart failure in these patients, perhaps SGLT2 inhibitors may also reduce the risk of atrial fibrillation. They explored the effect of Dapagliflozin on the first and total number of atrial fibrillation and atrial flutter events in patients from the DECLARE-TIMI 58. As a reminder, they had type two diabetes with either multiple risk factors for or known atherosclerotic cardiovascular disease. Now importantly, atrial fibrillation events were identified by a search of the safety database using these MedDAR preferred terms. Now what they found was Dapagliflozin reduced the risk of atrial fibrillation events during follow-up as well as the total number of atrial fibrillation events in patients with type two diabetes. These reductions were consistent across major subgroups including sex, presence of atherosclerotic cardiovascular disease, history of atrial fibrillation, history of heart failure, history of ischemic stroke, HBA1C groups, body mass index groups, blood pressure or EGFR. They looked at all these subgroups because these are all clinical factors, well established, with associations with the risk of atrial fibrillation. Dr Greg Hundley: Wow, Carolyn. Another sort of feather in the cap for the SGLT2 inhibitors. What does this mean for clinical practice? Dr Carolyn Lam: Ah. I'm not going to answer it here. I am going to say everybody has to read the excellent editorial by Dr Granger from Duke University and Dr Mahaffey from Stanford University School of Medicine. But what I will tell you is their concluding sentences. They said, "This report provides evidence that Dapagliflozin appears to reduce atrial fibrillation events in patients with diabetes and coronary disease and multiple risk factors. It also raises the issue of how to determine when effects on a secondary outcome, particularly one collected without the rigor of systematic collection using perspective definitions and case report forms, whether or not these are reliable." So must read. Dr Greg Hundley: Absolutely. Carolyn, my next study comes and evaluates arrhythmogenic right ventricular cardiomyopathy and is really investigating the concept of auto immunity, looking at associations of circulating anti heart and anti intercalated disc auto antibodies with disease severity and family history. The paper comes from Professor Alida Caforio from the University of Padova. Again, looking at the role of auto antibodies in patients with ARVC. An interesting topic. Dr Carolyn Lam: Yeah, that's really novel. What did they find? Dr Greg Hundley: They investigated ARVC pro bands, so those that sort of started with the disease process in a family and noted an increased frequency of serum organ specific anti heart autoantibodies and anti-intercalated disc autoantibodies in a sizeable arrhythmogenic RVC cohort as compared to controls. They found that positive AHA status. Dr Carolyn Lam: Anti-heart antibodies. Dr Greg Hundley: Yep. Was associated with lower left ventricular ejection fraction, a higher frequency of cardiac symptoms and implantable cardioverter defibrillator implantation. Positive AIDA was associated with lower ejection fractions in both the right and the left ventricle. Dr Carolyn Lam: AIDA being the anti-intercalated disc auto antibodies. Wow. That is interesting. But what are the clinical implications? Dr Greg Hundley: Well, the presence of both these organ specific AHA and AIDA antibodies provides evidence of autoimmunity in the majority, so 85% of familiar, and almost half, 45%, of sporadic ARVC. In programs and in effective relatives, these antibodies were associated with the disease severity features. So really a link with this auto immunity and ARVC. Dr Carolyn Lam: Yeah. I never thought of ARVC as an autoimmune disease. Very interesting. But let me also tell you what else is in this week's issue. There are letters to the editors, one from Dr Kaski regarding the mag STEMI randomized control trial questioning whether improving coronary vasal motion can be equated to restoring patient's cardiovascular health. Interestingly with a letter in response from Dr Sabatine. There's also a research letter by Dr Alahmad on the cardiovascular mortality and exposure to heat in an inherently hot region and where they were was Kuwait. They also drew some implications for climate change. Very interesting piece. There's also an ECG challenged by Dr Verma describing conduction abnormalities and ischemic cardiomyopathy in an 84-year-old man. Dr Greg Hundley: Very nice. Carolyn, in the mailbag, there's a nice research letter from Dr Nicholas Leeper from Stanford University School of Medicine. It's entitled “The 9p21 locus promotes calcific atherosclerosis.” Our own Josh Beckman has an on my mind piece regarding “The Big Mac Attack on Peripheral Arterial Disease.” Dr Carolyn Lam: I love that. I just love the titles Josh comes up with. Dr Greg Hundley: Then finally Bridget Kuehn has a very nice sort of correspondence on Cardiovascular News regarding cardiac imaging on the cusp of artificial intelligence. What a revolution we have ahead, Carolyn, and I know that's a topic that's true to your heart. Dr Carolyn Lam: It is. I loved her paper. Dr Greg Hundley: Okay. Carolyn, how about we get onto that feature article? I'm waiting to hear about the cost effectiveness of tafamidis. Dr Carolyn Lam: Me too. Dr Greg Hundley: Well listeners, we have got a great discussion for our feature publication today and we have Dr Dhruv Kazi from Beth Israel Deaconess in Boston and our own associate editor, Dr Justin Ezekowitz from University of Alberta. Well, as we get started, Kazi, can you tell us a little bit what was the hypothesis that you wanted to test with this study and maybe even before that a little bit of background with transthyretin amyloid and tafamidis? Dr Dhruv Kazi: Yeah. Transthyretin amyloidosis is a subgroup of patients who present with heart failure with preserved ejection fraction, which we know is a heterogeneous condition that has been pretty resilient to effective guideline directed therapies over the past decade. It's a subgroup of patients generally presenting in their 70s with slowly declining quality of life and a median survival of about three years. It hadn't had an effective therapy before and so when tafamidis, which is a stabilizer of transthyretin and prevents its deposition in the myocardium, was developed and tested in a randomized clinical trial that showed an improvement in survival, a reduction in heart failure hospitalizations and a slowing of decline and quality of life. It was viewed as a really big win for the heart failure community. What came as a surprise though is the pricing. It was launched in 2019 at $225,000 a year. We set out to ask, given that this is a severe disease without alternative treatments, is this price tag generating enough value? Is this a cost-effective therapy? The background here again is that oncologic therapies have had a long history of very high prices for rare diseases and severe diseases. But this is the first time we're seeing this in cardiology. Can we think more broadly about how we're going to tackle this issue? Not just for tafamidis but also for other drugs that come down the pipe. Dr Greg Hundley: Wow. $225,000 per year. Tell us what was your study design, and how did you go about evaluating this issue? Dr Dhruv Kazi: We started off with the one phase three trial of the drug that has been published and simulated in a mathematical model the population that would be eligible for this therapy, reproduced the events, heart failure hospitalizations, debts, quality of life that were seen in the trial for the first three years, and then extrapolated beyond the trial based on what we know about HFpEF and what we know about transthyretin amyloidosis. It's a mathematical model that first reproduces what was seen in the trial and then extrapolates beyond what we think is the best guess of what happens to these patients. We tested a variety of scenarios whether the drug continues to be effective, whether the effectiveness declines over time or the effectiveness ceases immediately after three years. Dr Greg Hundley: What did you find? Dr Dhruv Kazi: What we found was interesting and it surprised us a little bit, which is that in the base case, which is assuming that the drug stays effective beyond three years, the drug is actually very effective in the traditional sense. It added 1.3 quality adjusted life years. For context here, this is about twice the effect size you expect to see with Entresto, and the HFpEF patients. So here's a drug that we've accepted and HFpEF has part of guideline directed medical therapy. Tafamidis in that best-case scenario is about twice as effective, but it is not cost effective. Because you're paying $225,000 for every year that the patient is on the medication, its incremental cost effectiveness ratio compared with usual care was $880,000, so well above what we would consider value for money. That's the best-case scenario assuming that the drug is permanently effective, if the drug's effect wanes over time, which is very likely as these patients get older and sicker, then the drug gets even less economically attractive. Dr Greg Hundley: You've pointed out in your article, if you had 120,000 transthyretin patients in the United States, that would translate to how many dollars? Dr Dhruv Kazi: We estimate that if all of those 120,000 patients received tafamidis, the healthcare spending would go up by $32 billion a year and most of it is towards the drug. But the caveat is that we think 120,000 patients in the US is a very conservative number because the diagnostic technology for amyloid cardiomyopathy has improved substantially over the last five years so that we no longer need biopsies. We can use nuclear scans to diagnose the disease and we have pretty good to genetic testing to identify the genetic variant of the disease. We think that number is probably closer to 200,000 or even higher because the healthcare expenditure is almost entirely driven by drug costs. The more patients we diagnosed, the bigger the budget's impact on healthcare spending. Dr Greg Hundley: Oh my. Well Justin, for our listeners, Justin resides in Canada. Justin, what do we do with these results? I mean this is quite a sticker shock for probably an important therapy for this patient population. Dr Justin Ezekowitz: Greg, it's a great issue and Kazi, thank you very much for this terrific, easily understandable manuscript that I think everybody should read as it's very well written and easy to understand for us non-health economists. The sticker shock is a bit of a tricky one because we always want to do what's best for our patients. When we look at that budget impact analysis, the challenge is what do we think internationally? The US is critical in terms of understanding this, but then for the rest of the world, there's certainly almost no willingness to pay at this threshold and with an uncertain incidence of amyloidosis globally, but also within the US and Canada and the difficult in diagnosis already, I think we're going to have to realize what can we do for our patients and who benefits the most with this drug given its importance and its efficacy? Kazi, you mentioned another thing which I think is critical is what happens after 30 months if the effect wanes and where does that take us for the impact on cost and effectiveness over time but also the budget impact analysis? Because the second drug or third drug may very well come along that may fill that niche. Dr Dhruv Kazi: Justin, that's a really good question. I mean the study only goes to 30 months and that's the only one randomized trial for tafamidis that we're working off of. So there's substantial uncertainty about what happens to this drug beyond 30 months. It's reasonable to assume that some of the effect persists, that as patients get older, get sicker, that effectiveness will wane over time. Which ties very closely to the cost effectiveness. So if the patients continue to take the drug but it's not as effective as you can imagine, it becomes less cost effective. This also has implications for other drugs coming down the pike, which may or may not be more effective than tafamidis. They may or may not be tested head to head with tafamidis. Physicians are going to be left with the question, very clinically relevant question, of which drug to start with, how do you switch on them the next generation or more expensive drugs that come down the pike? We'll have to rely on both real-world evidence and to some extent mathematical modeling to use our best judgment on developing a treatment strategy for these patients. But rest assured that our current regulatory framework means that the drugs coming down in the future will be more expensive than tafamidis and hence, this is a good time to have the conversation about cost effectiveness and our willingness to pay for innovation. Dr Greg Hundley: What needs to happen next to help either lower cost or develop some sort of competition in the treatment of this disease to lower the cost? Dr Dhruv Kazi: I can take a stab at that. Greg, I think the findings of this particular drug in transthyretin amyloidosis is illustrative of the challenges that lie ahead. I think there are clinical research and policy implications. As clinicians, it's really important for us to know that this high cost of the drug is not a theoretical challenge. It's a practical challenge for our patients. The majority of these patients are going to be on Medicare part D. We estimate that the out of pocket costs is going to be in the range of $8,000 to $9,000 a year even with Medicare part D, which is a big amount of money for our fixed income seniors. I encourage our clinicians to have this conversation about out-of-pocket costs with patients, not just when you start the therapy but throughout the year. We know that the Medicare part D copays change over the course of the year based on where they are in the insurance plan. Having this conversation may help preclude costs related non-adherence. We might be able to identify patients early or at risk, put them into patient support programs or switch them to alternate therapies that may not be as effective but at least are likely to offer the patient some support. From a research perspective, we really need to figure out what subgroup of patients are more likely to benefit. Let's say we have 200,000 patients with transthyretin amyloidosis in the US. We need more research, and the company is not going to be vested in doing this research, it's going to have to be NIH funded research to identify subgroups of patients who benefit most from this drug, both in the short term and over the long term. From a policy perspective, what this drug pricing issue is telling us is that we provided incentives for companies to innovate in the rare disease orphan drug program. These incentives are working. More than half of the drugs that are coming out now or have in the past year are under this rare disease umbrella. But these drugs, once they're approved, are super expensive. We need to figure out a regulatory framework where we continue to incentivize innovation for rare diseases for orphan drugs, but at the same time tie those incentives to the final pricing to ensure that the patients get access to the drug and not just the wealthy patients who can afford the copays, but all patients who would benefit from the drug. One of the things that comes to mind as clinicians and researchers is that particularly in cardiology, we are obsessed with innovating, with regards to new molecules and new technology. I would like us as a community to focus not just on molecules but also on markets because the innovation is not meaningful if our patients cannot have access to them. This year being the presidential election year, we're going to hear a lot about drug pricing. What I hope that this example shines a light on is that drug pricing is complicated and trying to figure out the right framework to incentivize innovation while it's still ensuring access is going to take thoughtful interventions, regulatory interventions, and clinicians should very much be a part of that process. Dr Greg Hundley: Well listeners, we've heard a wonderful discussion here highlighting a new therapy for a disease process that's being increasingly diagnosed with our aging population and new technologies, magnetic resonance, echocardiography that identify this condition. But then how are we going to afford some of the therapies that are moving forward and design a system that emphasizes not only scientific discovery, but cost effectiveness? We want to thank Dr Dhruv Kazi from Beth Israel Deaconess and also Justin Ezekowitz from the University of Alberta. We hope you have a great week and look forward to speaking with you next week. This program is copyright the American Heart Association 2020.

We discuss transthyretin (aTTR) cardiac amyloidosis, symptoms, appropriate diagnostic testing and different treatment options available. Dr. Mathew Maurer from NewYork-Presbyterian Hospital/Columbia University shares his expertise with us. Listen, Like, Subscribe, and give us a rating!

Management of light chain or AL amyloidosis has changed with major advances in recent years. Dr. Ronald Witteles is a Stanford Cardiologist with particular expertise in the treatment of cardiac amyloidosis and shares his expertise with us. He serves as Co-Director of the Stanford Amyloid Center, one of the world's leading amyloid centers. Listen, Like, Subscribe, and give us a rating!

Therapy of Transthyretin Cardiomyopathy Dr Baliga's MUST KNOW FACTS PODCASTS FOR PHYSICIANS derived from a chapter authored by Taimur Sher, MD Faculty Hematologist & Associate Professor, Mayo Clinic, Jacksonville & Moire A Gertz, MD Emeritus Chair & Consult Hematologist, Mayo Clinic, Rochester, MN in Color Atlas and Synopsis of Heart Failure edited by RR Baliga, MD Series Editor: William T Abraham, MD McGraw Hill Education - Not Medical Advice or Opinion

Commentary by Dr. Valentin Fuster

Dr Greg Hundley               Welcome back everyone from our week hiatus for this July 2nd issue of Circulation On the Run. I'm Dr Greg Hundley, from the Pauley Heart Center at VCU health in Richmond, Virginia. Dr Carolyn Lam:                And I'm Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. So good to be back, Greg. Dr Greg Hundley               Absolutely. So Carolyn, our featured articles going to focus on amyloid and transthyretin amyloid is recognized in middle age and older individuals with increases in LV mass and heart failure. And in our featured article from the United Kingdom, Dr Gilmore and colleagues are going to discuss the natural history of this disease and compare outcomes of those with acquired versus hereditary forms of the disease. But before we get to that interview, how about we discuss several other original articles? Dr Carolyn Lam:                For sure, Greg. Thanks. I want to pick two genetic papers in this issue. They're really exciting. The first one is actually the first study to consider the association between rare genetic variance in a large set of cardiomyopathy genes and the occurrence of cancer therapy induced cardiomyopathy. So this paper is from co-corresponding authors, Dr Garcia-Pavia from hospital Universitario Puerta de Hierro from Madrid, and Dr Christine Seidman from Harvard Medical School in Boston, Massachusetts. The authors studied 213 patients with cancer therapy induced cardiomyopathy from three cohorts. The first retrospectively recruited adults with diverse cancers, the second prospectively phenotyped breast cancer patients. And then the third prospectively phenotyped children with acute myeloid leukemia. They showed an increased prevalence of rare variants in cardiomyopathy genes, particularly the truncating variants of the TTN gene in both adults and pediatric cancer patients with cancer therapy induced cardiomyopathy. They confirmed the human genetic data with experimental analyses showing that anthracyclines induced protracted left ventricular dysfunction in mice with truncating variants of TTN genes but not in the wild type mice. Dr Greg Hundley               Aha. So what are the clinical implications of this study, Carolyn? Dr Carolyn Lam:                Well, the findings show that variance in cardiomyopathy genes contribute to cancer therapy induced cardiomyopathy susceptibility among adult and pediatric cancer patients. And thus the identification of genetic risk factors really opens the door to new opportunities to define patients at high risk of cancer therapy induced cardiomyopathy and associated adverse outcomes.                                                 I want to go onto the next paper because it's so related. It's another genetic paper. This time looking further at the truncating variants of the TTN genes and a very novel approach, they aim to assess a genomics first approach to assess the consequences of these TTN variants. So, this was from corresponding author Dr Zoltan Arany from Perelman School of Medicine in University of Pennsylvania where he and his colleagues reviewed whole exome sequence data for more than 71,000 individuals to identify anyone with truncating variants of TTN genes. They further selected individuals with these variants in exons highly expressed in the heart and using a linked electronic health record, they evaluated the associations of these truncating variants of TTN genes with the diagnosis and quantitative echocardiographic measures. They also reviewed data from the Jackson Heart study to validate specific analyses for individuals of African ancestry. Dr Greg Hundley               Interesting. So we're hearing a little bit about different ancestry and TTN genes. What did they find? Dr Carolyn Lam:                So, I should have first clarified that that first look was in individuals of European ancestry. And they found there that the individuals of European ancestry identified through this genomics VERSE approach had a much greater odds of developing dilated cardiomyopathy and had lower left ventricular function than their peers, whether or not a clinical diagnosis of dilated cardiomyopathy was present. They also found that the association of the TTN variants and dilated cardiomyopathy was much weaker in individuals of African ancestry. So in summary, truncating genetic variants of TTN had a measurable effect in large clinical populations with respect to both strong associations with cardiomyopathy and with associations with quantitative differences in cardiac structure and function. Given the caveat though, that these association appeared strongest in individuals of European ancestry. So Greg, what did you have? Dr Greg Hundley               Well, Carolyn, the overlap of inflammatory processes operating in atherosclerosis and the rich presence of macrophages within plaques make macrophages a strong candidate for therapeutic targeting in atherosclerosis. And so this study comes from Levent Akyürek at the Institute of Biomedicine and involves targeting filament A to reduce macrophage activity in atherosclerosis. So filament A is a large actin binding protein that has been implicated in atherosclerosis and this study tested the hypothesis that targeting filament A in macrophages would impair atherosclerosis in vivo in mice and the investigators evaluated the expression of filament A in human atherosclerotic plaques. Dr Carolyn Lam:                Huh, interesting. So what did it show? Dr Greg Hundley:             Well, in humans, expression of filament A is increased in macrophages and advanced atherosclerotic plaques of human carotid arteries. In mice, in the absence of filament A, macrophages displayed impaired migration, proliferation and lipid uptake and secreted lower levels of inflammatory IL 6, also lack of filament A and macrophages in vivo reduced aortic plaque size and atherogenic mice.                                                 There were additional mechanistic findings and that the C terminal fragment of Filament A produced by calpain cleavage regulated IL 6 secretion in macrophages and treatment with calpeptin, which inhibits calpain cleavage, reduced aortic plaque size and atherogenic mice. And so therefore, filament A might serve as a prognostic biomarker and atherogenesis and perhaps targeting the C terminal proteolytic fragment of filament A could be a strategy to reduce inflammation and atherosclerotic plaque development. Carolyn, I've got another paper, but guess what? This one has our first quiz of the academic new year. This is a paper about Nexclin, and it discusses a new component of junctional membrane complexes required for cardiac T-tubule formation. The corresponding authors are led by professor Zhou Shen from the University of California, San Diego. So, Carolyn in this quiz, what is a T-tubule? Dr Carolyn Lam:                Greg, that is mean! T-Tubules, something inside the cell. Something to do with membranes folding over. Dr Greg Hundley               Yeah, you know this is one of those, it's not multiple choice. It's an open ended question. You need your little blue book. You've got to write the answer. So T, or transverse, tubules are extensions of the cell membrane that penetrate into the center of cardiac muscle cells and interact with the sarcoplasmic reticulum to facilitate calcium release and thus help modulate myocardial contraction. T-tubule uncoupling and remodeling are known features of heart failure. Dr Carolyn Lam:                Alright, so that's T-tubules. Guess what Greg, I'm going to ask you before you ask me. So, what's Nexilin? Dr Greg Hundley               I read the paper like a good student of the American Heart Association. This was answered by the investigative team of Chen and his associates. Nexilin has been identified as an actin binding protein and multiple mutations in the nexin gene are associated with cardiac diseases. In this study, Nexilin was required for initiation of T-tubule invagination and overall T-tubule formation, with a loss of next sullen leading to impaired calcium handling. Clinically, these results identified Nexilin as a new possible target for T-tubule remodeling and provide mechanistic insight into molecular pathways leading to cardiomyopathy in patients with mutations in Nexilin. So Carolyn, great job on our first quiz of the academic new year. And how about we move on to that featured discussion? Dr Carolyn Lam:                Absolutely. Dr Greg Hundley               Welcome everyone to our featured article discussion on this July 2nd and we are going to discuss with Dr Julian Gilmore from London, and our editor Dr Justin Grodin from Dallas, regarding amyloid. And Julian, I understand this particular study you have investigated a natural history of transthyretin amyloidosis cardiomyopathy. Can you tell us a little bit about transthyretin amyloid as opposed to light chain amyloid? And then also I think there's two types of transthyretin amyloid, both a hereditary and then a wild type. Dr Julian Gilmore:            Amyloidosis is a disorder of protein misfolding, and there are in fact many different proteins that can misfold and form amyloid fibrils. When they form fibrils they become insoluble and tend to build up and cause damage to whichever organ they're depositing in. Two of the proteins that form amyloid fibrils in humans in vivo are transthyretin, known as TTR for short, or immunoglobulin light chains, known as immunoglobulin light chains, and those two proteins cause transthyretin amyloidosis and AL amyloidosis or immunoglobulin light chain amyloidosis respectively. Those are the main two types of amyloid that affect the heart or cause a cardiomyopathy and they behave very differently in terms of their natural history in that AL amyloidosis is a very aggressive, rapidly fatal cardiomyopathy if untreated. Whereas cardiac transthyretin amyloidosis tends to be a more gradual albeit progressive cardiomyopathy.                                                 Transthyretin amyloidosis, as you alluded to, can either be acquired, known as wild type or hereditary and in the hereditary version it's associated with mutations in the transthyretin gene of which there are more than 130 now that are recognized to cause disease. The wild type version of the disease, the non-hereditary version of the disease, is now an increasingly recognized cause of heart failure, mainly in older individuals and particularly older males. And the hereditary version essentially remains a rather rarer disease, although the mutation that is associated or it is associated with a risk of developing this disease occurs in certain populations and in particular occurs in 4% of people of African descent, as a particular genetic mutation that occurs in 4% of individuals of African descent. So and that is associated with risk of developing this hereditary transthyretin cardiomyopathy. Dr Greg Hundley:             And so, there's the UK National Amyloidosis Center. Tell us a little bit from that center, what did you do with this particular study in terms of its design and what were your results? Dr Julian Gilmore:            Essentially the UK National Amyloidosis Center is the single center in the UK, which is commissioned centrally to diagnose and type, stage, and provide treatment FYS for patients with amyloidosis. And that includes all parts of amyloidosis. We studied a large number of patients with cardiac transthyretin amyloidosis, so cardiac ATTR amyloidosis, who referred to our center and studied them longitudinally, if you like, over the course of many years. So this was a natural history study for a condition for which at the time of the onset of the study and until the end of the study there was no disease modifying treatment and essentially what we found is that there was a great delay in diagnosis amongst most patients diagnosed with the disease and in fact the median number of attendances in hospital for patients diagnosed with the disease before they were actually diagnosed with 17 which is quite amazing and unsurprisingly in a gradually progressive disease, by the time they were diagnosed, their quality of life was very poor.                                                 We found that their quality of life symptoms gradually progressed and that they became more and more functionally impaired and had relatively poor survival with a median survival of somewhere in the region of five years. What we did find is that patients with a particular type of hereditary, ATTR amyloidosis, the type that I alluded to earlier, the mutation for which is present in 4% of people of African ancestry, he planted the V122I mutation. Patients carrying that particular mutation actually have more aggressive disease and survive for shorter than patients with the wild type disease.                                                 So, 17 hospitalizations before diagnosis and the proceeding three years. Were there factors in your study that you could identify that we should now be looking for to try and make this diagnosis earlier?                                                 Absolutely. So one of the reasons for not diagnosing the condition is basically the poor sensitivity and specificity of echocardiography, which is generally the first investigation that a cardiologist will request when a patient presents with symptoms of heart failure. There are some particular features on echocardiography that can provide clues such as strain measurement on tissue doppler imaging, where one can get a bullseye pattern, that's been reported in the literature. So there are particular features on echocardiography that one can look at to increase the chance of picking up this disease. And in particular the big increase in the number of diagnoses over recent years has been because of cardiac MRI scanning, which has become an increasingly used tool for the investigation of heart failure in which one gets a very characteristic picture of late gadolinium enhancement when it's performed in a patient with cardiac amyloidosis, which immediately triggers people to think, ah, here it is, we've got amyloid.                                                 And the other sort of novel diagnostic technique as being bone scintigraphy. In the UK we use a bone tracer called DPD and in the US a bone tracer called PYP, and those bone tracers have exquisite sensitivity for cardiac amyloidosis. So if one injects these tracers in a patient with cardiac amyloidosis one gets cardiac uptake into the heart, which can't really be missed on a planar scan. So those two techniques basically, the increasing needs of cardiac MRI and the increasing use of bone scintigraphy to investigate patients with heart failure have resulted in a great increase in the number of diagnoses.                                                 The last thing to say is that a huge proportion of patients with amyloid or transthyretin amyloid cardiomyopathy have actually had carpal tunnel syndrome previously. The median time from carpal tunnel syndrome to presentation with heart failure is about seven years, but that is another red flag, if you like, that ought to at least trigger a doctor to think could be amyloid. A thick walled heart in the context of someone whose had previous carpal tunnel syndrome. So there are a few clues there as to how one might make an earlier diagnosis, which is absolutely necessary given the nature of our data, sharing the delays that I outlined down here. Dr Greg Hundley               And Julian, last quick question before we get with Justin here. In your data, can you describe for us the importance of that earlier diagnosis related to long-term outcomes as opposed to the group that was diagnosed much later, you know, beyond your median. What was the difference in prognosis in those two groups? Dr Julian Gilmore:            There is no doubt that if patients are diagnosed earlier, they survived for longer, reflecting the natural history of the disease. So these patients, as I mentioned earlier, did not receive any disease modifying therapy and we did divide the patients into pre 2012, when patients were essentially diagnosed by endomyocardial biopsy, or the vast majority of them were diagnosed by endomyocardial biopsy, and post 2012 by which time most patients were diagnosed via an imaging, if you like, algorithm that we published in 2016 in the same journal in circulation. And the patients who were diagnosed earlier had significantly improved survival. Just corroborating really the fact that they were actually diagnosed earlier. What's particularly relevant there, is that the treatments that have been developed for this condition, and there are some recent new potential disease modifying treatments that have been developed, they find that things seem to slow progression of the disease rather than stop it or reverse it, so that if one can diagnose a patient early when their quality of life is still good and then slow progression, there's a high chance of improving quality of life quite substantially and obviously prolonging life. Dr Greg Hundley               Thank you so much, Julian. And Justin as the managing editor of this article, what struck you most in terms of its results and conclusions, and how we should manage patients today suspected of transthyretin amyloid? Dr Justin Grodin:              Well, I would say that really there are four things that in my opinion that were quite striking. The first at least as highlighted by Professor Gilmore is that the UK National Amyloid Center, they get the national case load. So this is unlike other cohorts and other centers across the world in that this is subject to less referral bias than others. So I think that's the first thing that's quite impressive. And I think Professor Gilmore really hit the nail on the head when he highlighted that this paper, that this analysis really underscores the importance of an early efficient diagnosis. And a lot of this is really through his seminal work in achieving a non-biopsy diagnosis of ATTR amyloidosis and his findings have been replicated in other cohorts as well. So I think those, I would like to say are really one and two.                                                 And then number three, which is one that I don't think Dr Gillmor mentioned, I think he mentioned indirectly, but we were also struck by the prognostic importance or I should say the prognostic meaning of having the V122I mutation. So these are individuals like hereditary amyloidosis and they have a single mutation. This is the one that is prevalent, at least we think from population studies, in approximately 4% of the African or Afro-Caribbean population. And we really see unequivocally that the time from symptom onset to diagnosis was shorter and the prognosis was actually worse in comparison to other mutations or in individuals with wild-type amyloid. And this is an important finding really for two reasons. Number one, it is largely confirmatory from other studies, but it's important to note that those studies were subject to referral bias. And we could never ever successfully incorporate whether or not socioeconomic status had actually influenced the bad outcomes of these individuals.                                                 And I would say that Professor Gilmore's findings are quite compelling in that regard. And then the second thing for this point is really this underscores I think the importance of genetic testing. I mean I think all the readers can take that message away. And then the fourth thing, which as Professor Gilmore alluded was the striking amounts of healthcare utilization, although it was in a minority, certainly quite compelling and really what it speaks to is multiple missed opportunities. Even in the UK where they have a centralized center of excellence, just like Professor Gilmore's, that there were delays in diagnosis and then when delayed these patients are quite ill. And I think I'm making all these points because at least in 2019, the regulatory environment about amyloidosis, specifically ATTR therapies. In The United States, it's actually changed. So a disease where we had therapies that might be off label or our therapies were largely symptomatic, where we managed the patient's signs and symptoms, we now actually have disease modifying therapies.                                                 So, in the United States in 2018, there were two biological agents that actually silence the livers production of transthyretin or TTR and they were approved for hereditary ATTR polyneuropathy. But there is some suggestion from sub-studies that those will have the efficacy in cardiac amyloid. And then number two in the United States, we recently gained approval in May of a drug that actually stabilizes the transthyretin protein or tetramer. So in other words, just as Professor Gilmore had highlighted at the beginning of this call, it stabilizes the breaking up, if you will, of this protein, which is the rate limiting step of amyloid formation. So you take this pill and then the transthyretin molecule does not then deposit amyloid. So this is really exciting because professor Gilmore's cohort study really captures now at least the impact that these therapies might have, and in the United States and across the world and in the UK, these therapies are being studied for all types of ATTR amyloid and really they're on the horizon. So it's given us very deep insights into how these might impact our patient's lives with ATTR. Dr Greg Hundley               Julian, Justin, that was just such an impressive discussion of a very important topic and something that again, with echocardiography, we really need to start thinking about when perhaps we appreciate some LVH, diastolic dysfunction. We have apical sparing of systolic function, but abnormal basal systolic function. Could you just summarize one point, each of you, that we should be thinking about as we move forward and we're seeing patients in our clinic that might have this disorder. Dr Justin Grodin:              The first thing to say is that awareness is all important. You know, 25% of male individuals in autopsy studies over the age of 80 have ATTR amyloid deposits in their heart, and when one sees a thick walled heart in any situation, and particularly in an elderly individual, one needs to think, could this be, amyloid, that's the first thing. And the second thing I'd like to say is that if that thought occurs, which it should occur at a much earlier stage than it does probably in most cardiologists minds, then one should think about either a bone scan, which is a cheap, simple tests. The PYP scan in the US or DPD scan in the UK and or an MRI scan, which has a very characteristic picture in a patient with cardiac amyloidosis. So those would be my take home messages to try and improve early diagnosis.                                                 You know, I'd like to dovetail what Professor Gilmore had said cause he just about took the words out of my mouth and I would like to emphasize the first point in that the diagnosis of AL, we mentioned earlier, or an ATTR amyloidosis, really necessitates a very, very high index of suspicion. What do I mean by that? When somebody has a thick heart muscle and it's not explained by something else, in other words, they don't have a lifetime history of high blood pressure and they don't have high blood pressure seeing you, or maybe they don't respond adequately to standard heart failure therapies when something is not fitting, it's always incumbent to the treating clinician to think amyloid.                                                 I would also like to highlight some of the clues that Professor Gilmore had mentioned, that any individual with carpal tunnel syndrome or who might be hospitalized with heart failure, in other words, they have shortness of breath and swelling, and the squeeze of their heart is normal, or the ejection fraction is normal, that should increase your index of suspicion for amyloidosis. And then individuals that might've had lumbar canal surgery or really any issue impacting their tendons. And then they're now presenting with a thick heart muscle. That should be a clue. It doesn't necessarily mean it's diagnostic. In fact, the majority of those individuals might not have, or a large proportion, might not have ATTR amyloid, but it should certainly raise an eyebrow and then kind of allow the clinician to move forward with the evaluations that Professor Gilmore had mentioned. Dr Greg Hundley               Well, listeners, what a phenomenal discussion that we've had from Professor Julian Gilmore from London, and Dr Justin Grodin from Dallas, Texas, educating us on transthyretin amyloid and thinking about that early and being suspicious as we evaluate patients, particularly older individuals that are symptomatic with heart failure. Well, on behalf of Carolyn Lam, this is Greg Hundley. We look forward to seeing you next week. Have a great week. Dr Carolyn Lam                  This program is copyright American Heart Association 2019  

Commentary by Dr. Valentin Fuster

Mazen Hanna, MD, Co-Director of the Cleveland Clinic’s Amyloidosis Center talks about the FDA’s recent approval of the drug Tafamidis for the treatment of ATTR Amyloidosis (also known as Amyloid Transthyretin Amyloidosis), the research behind it, what this medication does, and what this means for patients.

Mazen Hanna, MD, Co-Director of the Cleveland Clinic’s Amyloidosis Center talks about the FDA’s recent approval of the drug Tafamidis for the treatment of ATTR Amyloidosis (also known as Amyloid Transthyretin Amyloidosis), the research behind it, what this medication does, and what this means for patients.

Transthyretin is a protein found in the blood. Its name reflects its function, which is to transport thyroxine and retinol. In the case of a number of rare conditions, the protein becomes unstable and misfold, causing it to accumulate as toxic protein deposits in the heart or peripheral nerves. Eidos Therapeutics, a subsidiary of BridgeBio, is developing an experimental small molecule drug that binds and stabilizes transthyretin in the blood. We spoke to Jonathan Fox, chief medical officer of Eidos, about the rare diseases it is targeting, the treatments available today, and how it may change the landscape for these conditions.

Dr. Mazen Hanna describes the findings of ATTR-ACT, a study aimed at the treatment of transthyretin (TTR) amyloid cardiomyopathy with the medication tafamadis. Those who were treated with the medication had reduced mortality, hospitalizations, and better functional capacity and quality of life. This is an exciting new breakthrough for patients with TTR amyloidosis.

Commentary by Dr. Valentin Fuster

Dr. Ted Burns interviews Drs. Adam Loavenbruck and Phillip Low about their article "Transthyretin amyloid neuropathy has earlier neural involvement but better prognosis than primary amyloid counterpart: an answer to the paradox?" One hundred one cases of amyloidosis with peripheral neuropathy were identified, 60 primary and 41 transthyretin. Twenty transthyretin cases were found to have Val30Met mutations; 21 had other mutations. Compared to primary cases, transthyretin cases had longer survival, longer time to diagnosis, higher composite autonomic severity scale scores, greater reduction of upper limb nerve conduction study amplitudes, more frequent occurrence of weakness, and later non-neuronal systemic involvement. Four systemic markers (cardiac involvement by echocardiogram, weight loss > 10 pounds, orthostatic intolerance, fatigue) in combination were highly predictive of poor survival in both groups. Their findings suggest that transthyretin has earlier and greater predilection for neural involvement and more delayed systemic involvement. The degree and rate of systemic involvement is most closely related to prognosis. Ann Neurol 2016;80:401-411.

Dr. Ted Burns interviews Drs. Adam Loavenbruck and Phillip Low about their article "Transthyretin amyloid neuropathy has earlier neural involvement but better prognosis than primary amyloid counterpart: an answer to the paradox?" One hundred one cases of amyloidosis with peripheral neuropathy were identified, 60 primary and 41 transthyretin. Twenty transthyretin cases were found to have Val30Met mutations; 21 had other mutations. Compared to primary cases, transthyretin cases had longer survival, longer time to diagnosis, higher composite autonomic severity scale scores, greater reduction of upper limb nerve conduction study amplitudes, more frequent occurrence of weakness, and later non-neuronal systemic involvement. Four systemic markers (cardiac involvement by echocardiogram, weight loss > 10 pounds, orthostatic intolerance, fatigue) in combination were highly predictive of poor survival in both groups. Their findings suggest that transthyretin has earlier and greater predilection for neural involvement and more delayed systemic involvement. The degree and rate of systemic involvement is most closely related to prognosis. Ann Neurol 2016;80:401-411.

Transthyretin Amyloid Neuropathy has Earlier Neural Involvement but Better Prognosis than Primary

1) Emerging temporal trends in tissue plasminogen activator use: Results from the BASIC project2) e-Pearl topic: Transthyretin familial amyloid polyneuropathy3) Topic of the month: How to examine and approach movement disordersThis podcast for the Neurology Journal begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Kevin Barrett interviews Dr. Lynda Lisabeth about her paper on temporal trends in tissue plasminogen activator administration for acute ischemic stroke. Dr. Ilena George is reading our e-Pearl of the week about transthyretin familial amyloid polyneuropathy. In the next part of the podcast Dr. Jeff Ratliff interviews Dr. Ruth Walker on the topic of chorea.DISCLOSURES: Dr. Barrett serves as Associate Editor for Neurohospitalist; serves as an editorial board member for Neurology®; receives royalties from the publication of the book Stroke and editing the book Neurology in Practice; and receives research support from the NIH.Dr. Lisabeth receives research support from the NIH.Dr. George serves on the editorial team for the Neurology® Resident and Fellow Section. Dr. Walker is a consultant for Neurocrine Biosciences, Inc.; assists with Audio-Digest Board Reviews; received funding for travel from Korean Movement Disorders Society and honoraria from Neurocrine Biosciences, Inc.

Commentary by Dr. Valentin Fuster

Amyloid beta deposition in the brain is the hallmark of Alzheimers disease. Co-deposition of other amyloidogenic proteins like transthyretin, human cystatin C have been found in the plaques along with A beta. Revealing the details of the interaction between these proteins with A beta peptide in vitro is able to provide insight into finding new therapies for the disease.

Bei geschwächter Abwehrlage wird die Morbidität und Mortalität wesentlich von pulmonalen Komplikationen mitbestimmt. Ein Ziel dieser Arbeit war es, die Zusammensetzung und Funktion des pulmonalen Surfactants unter diesen Bedingungen zu untersuchen. Dazu wur-den die bronchoalveolären Lavageflüssigkeiten von Kindern mit malignen Erkrankungen, Immunsuppression, pulmonalen Infiltraten und therapieresistentem Fieber mit denen von pulmonal gesunden Kindern verglichen. Die SP-A-Konzentration war in der Patientengruppe deutlich erhöht, seine Funktion schien jedoch kaum verändert. Während auch die Werte für das SP-C und die kleinen Surfactant-Aggregate bei den Patienten deutlich erhöht waren, gab es kaum Unterschiede bei SP-B, SP-D, den großen Surfactant-Aggregaten und der Oberflächenaktivität. Diese Daten lassen eine adaptiv gesteigerte lokale Abwehr und ein System zur Erhaltung der Oberflächenaktivität unter den beschriebenen klinischen Bedingungen vermuten. Das zweite Ziel dieser Arbeit war die Entwicklung einer Methode zur Visualisierung von humanem SP-C mittels Immundetektion nach Dünnschichtchromatographie und Gelelektro-phorese. Eine quantitative Darstellung des SP-C in Lavageflüssigkeiten war mit keinem der beiden Verfahren möglich, eine empfindliche semiquantitative Detektion von rekombinan-tem SP-C mittels Dünnschichtchromatographie konnte jedoch erreicht werden. Ein weiteres Ziel war es, die Lavageproteine von pulmonal gesunden Kindern und Patienten gemäß ihrem Molekulargewicht und ihrem isoelektrischen Punkt zweidimensional darzustel-len, zu vergleichen und die besonders bei Kindern sehr begrenzten Mengen an Lavageflüs-sigkeit besser nutzbar zu machen. Folgende signifikante Änderungen wurden beobachtet: Bei den Patienten war das a1-Antitrypsin vermehrt, der Anteil an Ig-bindendem Faktor, Transthyretin und Cystatin S schien jedoch vermindert zu sein. Im Bereich der kleinen sauren Proteine behinderte der relativ hohe Anteil an Immunglobulinketten die Separation und Identifikation einzelner Proteine. Diese Daten zeigen, dass es bei Kindern mit malig-nen Erkrankungen, Immunsuppression, pulmonalen Infiltraten und therapieresistentem Fieber deutliche Veränderungen in der Zusammensetzung der bronchoalveolären Lavage-flüssigkeit gibt. Eine Vorfraktionierung der Proben könnte für die Identifikation der einzelnen Proteine ebenso hilfreich sein wie die Verwendung eines eng begrenzten pH-Bereiches bei der isoelektrischen Fokussierung. Diese Arbeit charakterisiert funktionelle und biochemische Aspekte des pulmonalen Sur-factantsystems bei Kindern mit malignen Erkrankungen, Immunsuppression, pulmonalen Infiltraten und therapieresistentem Fieber.