POPULARITY
View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter Ralph DeFronzo is a distinguished diabetes researcher and clinician whose groundbreaking work on insulin resistance has reshaped the understanding and treatment of type 2 diabetes. In this episode, Ralph shares insights from his five decades of research, including his pivotal role in bringing metformin to the U.S. and developing SGLT2 inhibitors. Ralph explores the impacts of insulin resistance on specific organs, the pharmacologic interventions available, and the gold-standard euglycemic clamp method for measuring insulin resistance. This episode is a masterclass in the pathophysiology and treatment of type 2 diabetes, featuring an in-depth discussion of GLP-1 receptor agonists, metformin, and a lesser-known class of drugs that opened Peter's eyes to new possibilities in diabetes care. We discuss: Metabolic disease as a foundational driver of chronic illness [4:00]; Defining insulin resistance: effects on glucose, fat, and protein metabolism, and how it varies between healthy, obese, and diabetic individuals [8:15]; The historical significance of the development of the euglycemic clamp technique for measuring insulin resistance [11:45]; How insulin affects different tissues: liver, muscle, and fat cells [15:00]; The different ways insulin resistance manifests in various tissues: Alzheimer's disease, cardiovascular disease, and more [25:00]; The dangers of hyperinsulinemia, and the importance of keeping insulin levels within a physiological range [29:00]; The challenges of identifying the genetic basis of insulin resistance and type 2 diabetes [37:00]; The “ominous octet”—a more comprehensive model of type 2 diabetes than the traditional triumvirate [45:45]; The kidneys' unexpected role in worsening diabetes, and how SGLT2 inhibitors were developed to treat diabetes [55:45]; How insulin resistance in the brain and neurocircuitry dysfunction contribute to overeating and metabolic disease [1:04:15]; Lipotoxicity: how overeating fuels insulin resistance and mitochondrial dysfunction [1:07:30]; Pioglitazone: an underappreciated and misunderstood treatment for insulin resistance [1:10:15]; Metformin: debunking the misconception that it is an insulin sensitizer and explaining its true mechanism of action [1:19:15]; Treating diabetes with triple therapy vs. the ADA approach: a better path for diabetes management [1:24:00]; GLP-1 agonists, the Qatar study, and rethinking diabetes treatment [1:31:30]; Using a hyperglycemic clamp to look for genes that cause diabetes [1:45:15]; The superiority of measuring C-peptide instead of insulin to assess beta-cell function [1:46:45]; How GLP-1-induced weight loss affects muscle mass, the benefits and risks of myostatin inhibitors, and the need for better methods of evaluating functional outcomes of increased muscle mass [1:51:30]; The growing crisis of childhood obesity and challenges in treating it [2:02:15]; The environmental and neurological factors driving the obesity epidemic [2:07:30]; The role of genetics, insulin signaling defects, and lipotoxicity in insulin resistance and diabetes treatment challenges [2:11:00]; The oral glucose tolerance test (OGTT): detecting early insulin resistance and beta cell dysfunction [2:18:30]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube
Real Life Pharmacology - Pharmacology Education for Health Care Professionals
Prednisolone is a corticosteroid that is often used in pediatrics. Hyperglycemia, insomnia, and GI upset are relatively common adverse effects. Ibuprofen is a commonly used OTC pain reliever. It is classified as an NSAID and can increase GI bleed risk and exacerbate heart failure. Aceon is the brand name for perindopril. ACE inhibitors are well known to cause drug induced cough and will cause hyperkalemia. Trazodone is classified as an antidepressant but is frequently used to treat insomnia because of its sedative properties. Pioglitazone is an oral anti-diabetes medication that should be avoided in patients with heart failure.
BUFFALO, NY- January 16, 2025 – A new #research paper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 22 on December 2, 2024, entitled “Less frequent skin ulcers among patients with Werner syndrome treated with pioglitazone: findings from the Japanese Werner Syndrome Registry.” Scientists from Chiba University in Japan and other institutions have discovered that the drug pioglitazone, commonly used to treat diabetes, may help prevent painful skin ulcers in people with Werner syndrome. Werner syndrome is a rare genetic condition that causes people to age faster than normal, leading to early gray hair, cataracts, and other age-related health problems. One of the most serious complications is skin ulcers, which affect nearly 70% of people with the disorder and can lead to severe pain, infections, and even amputations. The study, led by first author Kazuto Aono and corresponding author Masaya Koshizaka, looked at 51 patients with Werner syndrome from the Japanese Werner Syndrome Registry. Over half of the patients had skin ulcers, and those with ulcers were generally older and had higher blood pressure. The research team found that patients who took pioglitazone were much less likely to have ulcers, even after accounting for age. The research suggests that pioglitazone's ability to reduce inflammation helps wounds heal faster and prevents ulcers from forming. However, since the drug can cause side effects, like weaker bones, scientists recommend further studies to explore safer options, such as creams or gels made from pioglitazone that can be applied directly to the skin. “Nanostructured hybrid materials loaded with pioglitazone are also being developed for clinical use and may be useful as wound dressings for ulcer treatment.” Although the study shows promising results, the authors emphasize that more long-term studies are needed to confirm how effective the treatment is besides the exploration of other factors, like diet and exercise, that may also help reduce the ulcers. In conclusion, this study presents pioglitazone as a potential option to prevent skin ulcers in Werner syndrome patients. While further studies are needed, these findings provide hope for better treatments. DOI - https://doi.org/10.18632/aging.206161 Corresponding author - Masaya Koshizaka - overslope@chiba-u.jp Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.206161 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, Werner syndrome, skin ulcer, metformin, pioglitazon, progeroid syndrome About Aging-US The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population. The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.) Please visit our website at https://www.Aging-US.com and connect with us: Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM
In this episode, Arun B. Jesudian, MD, and Mazen Noureddin, MD, MHSc, discuss the expert-informed clinical pathway for the multidisciplinary care of patients with MASLD or MASH, current and emerging therapeutics, and management optimization strategies. Presenters:Arun B. Jesudian, MDAssociate Professor of Clinical MedicineDivision of Gastroenterology and HepatologyWeill Cornell MedicineNew York, New YorkMazen Noureddin, MD, MHScProfessor of MedicineHouston Methodist HospitalDirector Houston Research InstituteHouston, TexasContent based on an online CME program supported by independent educational grants from Novo Nordisk.To view the full program on “Clinical Pathways: Multidisciplinary Approach to Managing Metabolic Dysfunction‒Associated Steatohepatitis,” including 4 CME/CE-certified text modules with accompanying slidesets, 4 ClincalThought commentaries, and a downloadable infographic resource on the AGA MASLD MASH Clinical Care Pathway, visit clinicaloptions.com or click on the link below.Link to full program:https://bit.ly/3Tyu7At
In this episode, Arun B. Jesudian, MD, and Mazen Noureddin, MD, MHSc, discuss the expert-informed clinical pathway for the multidisciplinary care of patients with MASLD or MASH, current and emerging therapeutics, and management optimization strategies. Presenters:Arun B. Jesudian, MDAssociate Professor of Clinical MedicineDivision of Gastroenterology and HepatologyWeill Cornell MedicineNew York, New YorkMazen Noureddin, MD, MHScProfessor of MedicineHouston Methodist HospitalDirector Houston Research InstituteHouston, TexasContent based on an online CME program supported by independent educational grants from Novo Nordisk.To view the full program on “Clinical Pathways: Multidisciplinary Approach to Managing Metabolic Dysfunction‒Associated Steatohepatitis,” including 4 CME/CE-certified text modules with accompanying slidesets, 4 ClincalThought commentaries, and a downloadable infographic resource on the AGA MASLD MASH Clinical Care Pathway, visit clinicaloptions.com or click on the link below.Link to full program:https://bit.ly/3Tyu7At
Host: John Buse, MD, PhD Guest: David Spence, MD Pioglitazone was studied in the Insulin Resistance Intervention after Stroke trial, or IRIS for short. What do we need to know about it? Joining Dr. John Buse to share background and clinical data of the impacts observed is Dr. David Spence, a Professor Emeritus of Neurology and Clinical Pharmacology at Western University and the Director of the Stroke Prevention and Atherosclerosis Research Center in London, Ontario.
Co-authors Ken Cusi and Stephen Harrison discuss reasons to be optimistic and activist about the multidisciplinary call to action regarding the coming NASH Epidemic while NASH kNOWledge President Anthony Villiotti, Global Liver Institute Director of Global Policy Andrew Scott and Roger Green share their unique personal perspectives and Louise Campbell comments separately.This conversation starts with Stephen Harrison suggesting messages for the government and Roger Green and Andrew Scott considering new opportunities to create metrics and benchmarks to measure success. All this relates to the effort in bring gastroenterologists, endocrinologists, hepatologists and primary care physicians together to fight what they describe as the coming NASH Epidemic. Paper co-authors Ken Cusi and Patient Advocates Tony VIlliotti and Louise Campbell share their own views (Louise's statement were extracted from a separate interview).
Co-authors Ken Cusi and Stephen Harrison discuss how the multidisciplinary call to action regarding the coming NASH Epidemic came to be, while NASH kNOWledge President Anthony Villiotti, Global Liver Institute Director of Global Policy Andrew Scott and Roger Green share their unique personal perspectives and Louise Campbell comments separately.This conversation starts with Ken Cusi providing background on the effort to bring gastroenterologists, endocrinologists, hepatologists and primary care physicians together to fight what they describe as the coming NASH Epidemic. The other panelists offer observations from their diverse perspectives.
Co-authors Ken Cusi and Stephen Harrison discuss critical success factors in the multidisciplinary call to action regarding the coming NASH Epidemic while NASH kNOWledge President Anthony Villiotti, Global Liver Institute Director of Global Policy Andrew Scott and Roger Green share their unique personal perspectives and Louise Campbell comments separately.This conversation starts with Roger Green asking what it will take to bring gastroenterologists, endocrinologists, hepatologists and primary care physicians together to fight what they describe as the coming NASH Epidemic. Paper co-authors Ken Cusi and Stephen Harrison and Patient Advocates Tony VIlliotti, Andrew Scott and Louise Campbell share their own views (Louise's statement were extracted from a separate interview).
Co-authors Ken Cusi and Stephen Harrison discuss the multidisciplinary call to action regarding the coming NASH Epidemic, how the first paper came to be and what lies behind it, while NASH kNOWledge President Anthony Villiotti, Global Liver Institute Director of Global Policy Andrew Scott and Roger Green share their unique personal perspectives on the need for diverse health professionals to align against Fatty Liver disease.The first part of this episode addresses the history and key contents of the recent paper, "Preparing for the NASH Epidemic: A Call to Action," in press or appearing in several major journals:8:53 - Ken Cusi discusses the genesis and goals of the multi-disciplinary NASH initiative, which organizations participated and the questionnaire that lies at the heart of the paper. Stephen Harrison elaborates on goals and Tony Villiotti shares his perspective as a cirrhosis patient who underwent liver transplant13:34 - Stephen Harrison discusses the recent prevalence paper suggesting that current population estimates of NASH and NAFLD may be understated. Ken Cusi agrees.16:29 - CRITICAL SUCCESS FACTORS: Stephen Harrison discusses the dual needs for an approved drug and a consensus approach. Roger Green mentions the need to distribute care so that hepatologists are neither triage nor point of entry for NAFLD patients. Ken Cusi uses data from the 751-person survey to demonstrate how low NASH awareness is even among specialists (notably endocrinologists) and reaffirms the need for a therapy.23:08 - Stephen Harrison shifts the discussion to focus on promising signs for the future, including integration of key stakeholders' discussions and efforts, the ability to identify and create care metrics and the importance of story-telling in making a persuasive case to power centers ranging from medical organizations to Capitol Hill.31:37 - Discussion shifts to similarities and differences between treating diabetes and NAFLD and the role of the endocrinologist in each. Ken Cusi and Andrew Scott discuss why they believe diabetes is a good model for developing knowledge and treatment protocols. The group discusses ways that endocrinology might be fertile territory and, at the same time, will require significant professional education and increases in awareness.40:03 - Tony Villiotti return to the importance of story-telling and personal experiences as powerful motivating tools.41:51 - The group concludes by considering the tipping points and behavior changes we can drive today, before the first drug comes to market.MONEY QUOTE: "Roger, I've heard you say the liver is the Rodney Dangerfield of organs, and you know it's true." - Anthony Villiotti
One way to reduce or reverse arterial plaque is to improve one's blood glucose numbers. Can anti-diabetes medications metformin & pioglitazone help in this area? In this podcast, let's discuss: Ways to reverse arterial plaque; How metformin works;How pioglitazone works.For more information, contact us at 859-721-1414 or myhealth@prevmedheartrisk.com. Also, check out the following resources: PrevMed's article on arterial plaque reversalPrevMed's websitePrevMed's YouTube channelPrevMed's Facebook page
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.22.301762v1?rss=1 Authors: Geoffroy, A., Habbas, K., Zambo, B., Schramm, L., Duchon, A., Flatter, E., Fouillen, L., Zumsteg, J., Heintz, D., Mandel, J.-L., Herault, Y., Moine, H. Abstract: Fragile X syndrome (FXS), the leading cause of familial intellectual disability, is an uncured disease caused by the absence or loss of function of the FMRP protein. FMRP is an RNA binding protein that controls the translation of specific proteins in neurons. A main target of FMRP in neurons is diacylglycerol kinase kappa (DGKk) and the loss of FMRP leads to a loss of DGK activity causing a diacylglycerol excess in the brain. Excessive diacylglycerol signaling could be a significant contributor to the pathomechanism of FXS. Here we tested the contribution of DAG-signaling in Fmr1-KO mouse model of FXS and we show that pioglitazone, a widely prescribed drug for type 2 diabetes, has ability to correct excessive DAG signaling in the brain and rescue behavioral alterations of the Fmr1-KO mouse. This study highlights the role of lipid signaling homeostasis in FXS and provides arguments to support the testing of pioglitazone for treatment of FXS. Copy rights belong to original authors. Visit the link for more info
BLACK BOX WARNINGS ⚠️ : 1. Pioglitazone & rosiglitazone Worsen CHF & fluid retention . 2. METHADONE : respiratory depression
Swim through the sea of acronyms as Dr Scott Matherly (@liverprof) helps us become a little less baffled by the thought of NAFLD. We discuss the initial diagnosis of fatty liver disease, indications for additional evaluation with imaging and/or biopsy, and potential treatment options. With a quarter of the world affected, it’s crucial to understand the various forms of disease and how to counsel patients about this all-too-common condition! Listeners can claim Free CE credit through VCU Health at http://curbsiders.vcuhealth.org/ (CME goes live at 0900 ET on the episode’s release date). Show Notes | Subscribe | Spotify | Swag! | Top Picks | Mailing List | thecurbsiders@gmail.com | Free CME! Credits Written and Produced by: Elena Gibson MD Infographic and Cover Art: Elena Gibson MD Hosts: Matthew Watto MD, FACP; Paul Williams MD, FACP Editor: Emi Okamoto MD (written materials); Clair Morgan of nodderly.com Guest: Scott Matherly MD Sponsors Pediatrics On Call podcast by the American Academy of Pediatrics If you provide medical care to children, Pediatrics On Call — the new podcast from the American Academy of Pediatrics — will help you do it better. Each week, hear the latest news and research on children's health, on topics from obesity and mental health to keeping the kiddos safe when they’re stuck at home. Subscribe from your favorite podcast provider or find the latest episodes here. VCU Health CE We are excited to announce that the Curbsiders are now partnering with VCU Health Continuing Education to offer continuing education credits for physicians and other healthcare professionals. Check out curbsiders.vcuhealth.org and create your FREE account! Time Stamps 00:00 Sponsors - VCU Health Continuing Education and the AAP’s Pediatrics On Call podcast 00:30 Intro, disclaimer, guest bio 03:15 Guest one-liner; Picks of the Week* : 08:15 Sponsor - the AAP’s Pediatrics On Call podcast 08:50 Case from Kashlak part 1; What is hepatic steatosis? 11:43 NAFLD acronyms and definitions 18:20 Alcohol and Fatty Liver 23:15 Initial Evaluation of NAFLD 35:12 Dr Matherly’s piel to patients with fatty 41:11 NASH/Fibrosis Risk Assessment 48:54 Outcomes in NASH with Fibrosis 51:20 Statins are safe in liver disease 56:15 Treatment Options (surgery, Vitamin E, Pioglitazone, SLGT2 inhibitors and GLP1 agonists; Coffee?!) 71:42 Take home points and Outro Links* Episode 100: Cirrhosis Initial Evaluation and Management Episode 101: Cirrhosis Medications, Decompensation, Complications The Last of Us Part II Not a Diet Book by James Smith Fooled by Randomness by Nassim Nicholas Taleb Beirut Band - Gallipoli and The Flying Club Cup Beat Saber *The Curbsiders participates in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising commissions by linking to Amazon. Simply put, if you click on our Amazon.com links and buy something we earn a (very) small commission, yet you don’t pay any extra. Goal Listeners will develop an approach to the basic evaluation and initial management of NAFLD. Learning objectives After listening to this episode listeners will… Recognize the different etiologies of hepatic steatosis Define terms: non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver (NAFL) non-alcoholic steatohepatitis (NASH), alcoholic steatosis, cryptogenic cirrhosis Define the risk factors associated with NAFLD Develop an approach to the initial evaluation and management of NAFLD and NASH Recognize the value of weight loss in the management of NAFLD Determine when and how to monitor patients for progression of NAFLD Identify pharmacologic treatment options for patients with NASH and recognize when and how to use them. Describe the outcomes of concern associated with NAFLD and NASH. Disclosures Dr Matherly reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. Citation Matherly S, Gibson EG, Williams PN, Okamoto E, Watto MF. “#227 Baffled by NAFLD”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list . Original air date July 27, 2020.
Hear Philip N. Newsome, PhD, FRCPE, discussavailable approaches to managing NASH, including lifestyle, vitamin E, and compounds that target insulin resistance, including:Recommended Pharmacologic Therapies for NASHPioglitazoneVitamin EOptimal Diabetes Therapies in NAFLD/NASHWeight LossLiver HealthSurgical Approaches to Weight Loss and Effect on LiverDownload the slides from this podcast at:https://bit.ly/3ig0r6xSee more NASH topics at:https://bit.ly/3ezkBq6
Hear Philip N. Newsome, PhD, FRCPE, discuss the agents in late-phase clinical trials and their potential use in the treatment of NASH and fibrosis, including those in phase III such as:Obeticholic acidCenicrivirocResmetiromAramcholDownload the slides from this podcast at:https://bit.ly/3eJYKvWSee more NASH topics at: https://bit.ly/3ezkBq6
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.24.168518v1?rss=1 Authors: Liu, Y., Hanson, K. A., McCormack, G., Dittmann, J., Vickers, J. C., Fernandez-Martos, C. M., King, A. E. Abstract: Background: Alzheimers disease (AD) has challenged single-target therapeutic strategies, raising the possibility that combined therapies may offer a more effective treatment strategy. Objective: There is substantial evidence for the efficacy of leptin (L) (neuroprotective hormone) and pioglitazone (P) (anti-inflammatory agent) as monotherapies in AD. We have previouly shown that combination treatment of L+P in APP/PS1 mice at the onset of pathology significantly improved memory and reduced brain Abeta levels relative to control mice. In this new study, we sought to replicate our previous findings in a new cohort of APP/PS1 mouse to further confirm whether the combined treatment of L+P is superior to each treatment individually. Methods: We have re-evaluated the effects of L+P co-treatment in APP/PS1 mice using thioflavin-S staining, MOAbeta immunolabeling and enzyme-linked immunosorbent assay (ELISA) to examine effects on Abeta levels and pathology, relative to animals that received L or P individually. To explore mechanism of regulation, we used Western blotting to examine the expression of the peroxisome-proliferator activated receptor gamma (PPARgamma), due to its potential role in the regulation of the inflammatory response. Results: We demonstrated that combining L and P significantly enhances the anti-Abeta effect of L or P in the hippocampus of APP/PS1 mice. Western blot analysis indicated that Abeta reduction was accompanied by up-regulation of the PPARgamma levels. Conclusion: Our findings suggest that combining L and P significantly enhances the anti-Abeta effect of L or P in the hippocampus of APP/PS1 mice, and may be a potential new effective strategy for AD therapy. Copy rights belong to original authors. Visit the link for more info
Diabetes Core Update is a monthly podcast that presents and discusses the latest clinically relevant articles from the American Diabetes Association’s four science and medical journals – Diabetes, Diabetes Care, Clinical Diabetes, and Diabetes Spectrum. Each episode is approximately 20 minutes long and presents 5-6 recently published articles from ADA journals. Intended for practicing physicians and health care professionals, Diabetes Core Update discusses how the latest research and information published in journals of the American Diabetes Association are relevant to clinical practice and can be applied in a treatment setting. This month we review articles on: Dapagliflozin Plus Saxagliptin Add-on Therapy Compared with Insulin Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND) Mediterranean Diet and the Need for Glucose- Lowering Medications Oral Semaglutide versus Subcutaneous Liraglutide and Placebo Vitamin E and Pioglitazone for Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes Durability of Insulin Degludec plus Liraglutide versus Insulin Glargine U100 For more information about each of ADA’s science and medical journals, please visit www.diabetesjournals.org. Presented by: Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health John J. Russell, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Director, Family Medicine Residency Program, Abington Jefferson Health
Real Life Pharmacology - Pharmacology Education for Health Care Professionals
On this episode, I cover pioglitazone pharmacology. The primary mechanism of action with pioglitazone is that it is an agonist at Peroxisome Proliferator Activated Receptor Gamma receptor. This improves insulin sensitivty in the periphery. Two common side effects exist with pioglitazone. This drug can cause weight gain and also contribute to edema. Pioglitazone has a boxed warning and is contraindicated in patients who have symptomatic heart failure. There are a few potential interactions with pioglitazone. Trimethoprim and gemfibrozil can inhibit the breakdown of pioglitazone. A couple of advantages of pioglitazone include that it is generic (inexpensive) and that it is dosed once daily.
In this episode I cover type 2 diabetes.If you want to follow along with written notes on hyperthyroidism go to zerotofinals.com/type2diabetes or find the endocrinology section in the Zero to Finals medicine book.This episode covers the pathophysiology, presentation, investigations, diagnosis and management of type 2 diabetes. We also look at all the individual medications used in type 2 diabetes and the different types of insulin.
New data reinforce the perils of opiate use in IBD patients. Researchers find that non-CDI enteric infections are uncommon triggers of flares in IBD patients. Pioglitazone is effective for treating NASH in patients with or without diabetes. Hypothetical biomarker test with substantially better performance than FIT would be more cost-effective than FIT if its cost doesn't exceed $57.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. This week's journal features two papers that deal with genetic testing in young athletes and for sudden arrhythmic death, and with findings that may surprise you. They really show the complexities of this era of genetic testing and cardiovascular medicine, and in fact are discussed as growing pains in cardiovascular genetics. You must listen to our feature discussion, which is coming right up after these summaries. The first original paper this week suggests that targeting fibronectin polymerization may be a new therapeutic strategy for treating cardiac fibrosis. Fibronectin polymerization is necessary for collagen matrix deposition and is a key contributor to increased abundance of cardiac myofibroblast following cardiac injury. In today's paper, first author Dr Valiente-Alandi, corresponding author Dr Blaxall from University of Cincinnati College of Medicine and Heart Institute, and their colleagues hypothesized that interfering with fibronectin polymerization, or its genetic ablation and fibroblasts, would attenuate myocardial fibrosis and improve cardiac function following ischemia reperfusion injury. Using mouse and human cardiac myofibroblasts, authors found that the fibronectin polymerization inhibitor pUR4 attenuated the pathological phenotype exhibited by mouse and human myofibroblasts by decreasing fibronectin polymerization and collagen deposition into the extracellular matrix as well as by myofibroblast proliferation and migration. Inhibiting fibronectin matrix deposition by pUR4 treatment or by deleting fibronectin gene expression in cardiac fibroblasts confirmed cardioprotection against ischemia reperfusion-induced injury by attenuating at first left ventricular remodeling and cardiac fibrosis, thus preserving cardiac function. In summary, interfering with fibronectin polymerization may be a new therapeutic strategy for treating cardiac fibrosis and heart failure. The Insulin Resistance Intervention after Stroke, or IRIS trial, demonstrated that pioglitazone reduced the risk of both cardiovascular events and diabetes in insulin-resistant patients. However, concern remains that pioglitazone may increase the risk of heart failure in susceptible individuals. To address this, Dr Young from Yale Cardiovascular Research Center and the IRIS investigators performed a secondary analysis of the IRIS trial. They found that older age, atrial fibrillation, hypertension, obesity, edema, high CRP, and smoking were risk factors for heart failure. Pioglitazone did not increase the risk of incident heart failure, and the effect of pioglitazone did not differ across levels of baseline risk. It should however be noted that in the IRIS trial, the study drug dose could be reduced for symptoms of edema or excessive weight gain, which occurred more often in the pioglitazone arm. Overall, pioglitazone reduced the composite outcome of stroke, MI, or hospitalized heart failure in the IRIS trial. The next study highlights the importance of genetic variation in cardiac fibrosis and suggests that while fibroblast activation is a response that parallels the extent of scar formation, proliferation may not necessarily correlate with levels of fibrosis. In this paper from co-first authors Dr Park and Ranjbarvaziri, corresponding author Dr Ardehali, from David Geffen School of Medicine, University of California, Los Angeles, the authors utilized a novel multiple-strain approach known as the Hybrid Mouse Diversity Panel to characterize the contributions of cardiac fibroblasts to the formation of isoproterenol-induced cardiac fibrosis in three strains of mice. They found that isolated cardiac fibroblasts treated with isoproterenol exhibited strain-specific increases in the levels of activation, but showed comparable levels of proliferation. Similar results were found in vivo with fibroblast activation but not proliferation correlating with the differential levels of cardiac fibrosis after isoproterenol treatment. RNA sequencing revealed that cardiac fibroblasts from each strain exhibited unique gene expression changes in response to isoproterenol. The authors further identified LTBP2 as a commonly upregulated gene after isoproterenol treatment. Expression of LTBP2 was elevated and specifically localized in the fibrotic regions of the myocardium after injury in mice and in human heart failure, suggesting that it may be a potential therapeutic target. That brings us to the end of our summaries. Now for our feature discussion. We all know that t-wave inversion is common in patients with cardiomyopathy, however up to a quarter of athletes of African descent, and five percent of white athletes also have t-wave inversion on ECG, but with unclear clinical significance despite comprehensive clinical evaluation. Now, what is the role in diagnostic use of genetic testing beyond clinical evaluation when we investigate these athletes with t-wave inversion? Well we're about to get some answers in today's feature paper, and I'm so pleased to have the corresponding author of the paper, Dr Sanjay Sharma from St. George's University of London, as well as our associate editor Dr Mark Link from UT Southwestern. Sanjay, please let us know what you did and what you found. Dr Sanjay Sharma: Well as you rightly say, that up to 25% of black athletes have t-wave inversion, as do three to five percent of white athletes. And these t-wave inversions often overlap with the sort of patterns that you see in patients with hypertrophic cardiomyopathy and arrhythmogenic cardiomyopathy. For example, 80% of people with hypertrophic cardiomyopathy have t-wave inversion as do 60% of patients with ARVC. Now we know that some ECG patterns, t-wave inversions in V1 to V4 are benign in black patients, but the significance of other ECG patterns is unknown. Cascade screening in family members with cardiomyopathy have shown that t-wave inversion may be the only manifestation of gene inheritance, and there are reports to suggest that some athletes with t-wave inversion do go on to develop overt cardiomyopathy. Now when we investigate the vast majority of our patients with t-wave inversion, these are our athlete patients, we don't actually find anything. But over the past decade, also, these has been major advance in next generation sequencing that allows us to perform genetic testing in a large number of genes that can cause diseases, capable of causing sudden death. And so, we thought we'd investigate the role of this gene testing in athletes with t-wave inversion. We looked at a hundred, 50 black athletes and 50 white athletes who had t-wave inversion, and we investigated them comprehensively with clinical tests. But we also added in a gene panel looking at 311 genes implicated in six cardiac diseases, notably hypertrophic cardiac myopathy, arrhythmogenic cardiomyopathy, dilated cardiomyopathy, left ventricular non-compaction, long QT syndrome, and the brugada syndrome. We found that 21% of our athletes were then diagnosed with a cardiac disorder capable of causing sudden death, and the vast majority of these people had hypertrophic cardiomyopathy. And this diagnosis was based on clinical evaluation. When we looked at gene testing, we found that gene testing only picked up a problem in 10%. So, the diagnostic yield of gene testing was half that of comprehensive clinical investigation. When we actually looked at athletes who had nothing wrong with them in clinical investigation, and actually had a gene mutation, we found that only 2.5% of athletes who had t-wave inversion but clinically normal tests, actually had something wrong with them. And our conclusions were that gene testing picks up only half the athletes that clinical testing does, and gene testing is only responsible for identifying 2.5% of athletes with t-wave inversion, where clinical tests are negative. That was the summary of our study in short. We did find that black athletes were less likely to have a positive diagnosis of cardiac myopathy than white athletes, and black athletes are also less likely to have a genetic mutation capable of causing a cardiomyopathy than white athletes. Dr Carolyn Lam: First and foremost, congratulations on such a beautiful paper, and so wonderfully summarized as well. It really seems to fly in the face, doesn't it? Of the way we've been discussing personalized medicine and saying that we're going to start whole genome sequencing everyone and that's going to provide all the answers for future disease risks. I mean, if I'm not wrong, what your paper is trying to tell us is that at this moment we don't have good examples where genetic testing may trump clinical diagnoses, and in fact we should be still focusing on a comprehensive clinical evaluation of patients and in the absence of a genotype we should learn to question what we're doing in genetic testing. Do you agree with that? Dr Sanjay Sharma: You couldn't have said that more precisely. As I've said, the diagnostic yield of clinical testing was 21% versus only 10% with genetic testing. The diagnostic yield of pure genetic testing in people with otherwise completely normal findings clinically was only 2.5%. And the other thing that I forgot to tell you was that genetic testing, if we included genetic testing in addition to comprehensive assessment, cost us three times as much as clinical investigation on its own, and had we relied solely on genetics, and nothing else, it would have cost us ten times more than clinical testing. So our cost per making a diagnosis using genetics only would have amounted to $30,000 per condition. Dr Carolyn Lam: Wow, what a great wake up call. Mark, you've thought a lot about this and in fact there was another paper in this week’s journal that has very complimentary messages. In fact you invited an editorial by Dan Roden, and I really loved his title of it, "Growing Pains in Cardiovascular Genetics." Would you maybe add your thoughts in relation to the other paper, as well as overall? Dr Mark Link: Sure. Circulation was very interested in these papers. These are really ... Now, as Dan Roden says, "Growing pains." Twenty years ago when genetics came out it was looked upon as it was going to completely change our clinical medicine and precision medicine is really relying a lot on genetics. And while ultimately that may be the case, we are in a stage now where the honeymoon is over. And the other paper that was in this same issue was a paper by Hosseini and colleagues, and it was the Clin Gen paper looking at the Brugada Syndrome abnormalities. Now the Clin Gen is an NIH sponsored group that takes individuals from a number of different institutions and actually gene testing, and tries to provide an independent assessment of the abnormality of genes. Previously is was companies that did this. A company would gene test ... They would look for gene abnormalities, try to link it with clinical disease, and they could basically then do just on their patients. But Clin Gen now is trying to tie all those companies together to get a broad consortion and to look at genetic abnormalities and whether they're truly pathologic, where there's areas of unknown significance, or whether they're truly not pathologic. So as an example, they took Brugada Syndrome, and they took the different gene abnormalities that have been described from basically different companies and different labs and different institutions, and they looked at the evidence behind the fact that they were truly pathologic, 'cause all 21 genes were defined as pathologic. They found in their independent assessment that only one ended up to be truly pathologic, and the others ones were disputed. And sort of another wakeup call that just because a single company calls a gene pathologic or Brugada Syndrome, does not make it pathologic necessarily. So we all thought these were two very important papers that looked at some of the limitations of genetic testing. We asked Dan Roden, who is really a very accomplished scholar in this field, to provide perspective on this. And I agree, I loved his title, "Growing Pains in Cardiovascular Genetics." And what he did is reviewed the history of genetic testing, and he actually starts before genetic testing and starts with Mendelian genetics, and [inaudible] genetics. And then 23 years ago they started linking that Mendelian genetics to gene abnormalities, especially in diseases such as long QT syndrome and hypertrophic cardiomyopathy. We've come a tremendous way in diagnosing gene abnormalities and associating them with these underlying cardiac myopathies and hind channel abnormalities. So no one doubts we've come a tremendous way, but there's a long way to go in terms of getting better diagnostic accuracy and really defining where these genetic testing are ultimately going to play out in clinical medicine. So everyone's excited about it, but I think these two papers are two cautionary tales that we do have to remember that genetic testing in 2018 is not the end all and be all. Dr Carolyn Lam: I love that, cautionary tales. So important. But where do we go from here? What's the take home message for clinicians listening to this today in 2018? I mean is it that perhaps when we do these things we now need to include medical geneticists and genetic counselors as vital partners as we look at this all? Perhaps we need to not forget the primacy of clinical evaluation. What do you think, Sanjay? Dr Sanjay Shar: Well, there are guidelines from the American Medical Genetics side as to what one defines as a disease-causing mutation. But I agree that we need to be using certified laboratories that can actually interpret the genetic mutations. For example, in our study of athletes, 63% actually had variance of undetermined significance. So they had spinning mistakes in their genes which probably didn't account to anything at all, but had these mutations, or these so called variance of undetermined mutations been interpreted by someone who didn't really know much about this, these could have resulted in false positive results which could cause absolute chaos for an athletes career. So I do think this type of testing has to be governed very, very carefully and needs to be performed in very specialized and certified laboratories. Dr Carolyn Lam: Indeed. Not just to the athlete, but to their families too, isn't it? Mark, what do you think is the take home message [inaudible 00:16:18]? Dr Mark Link: I think one of the big take home messages that I took away from these papers is that clinical medicine is not dead. In fact, clinical medicine in this day and age is still the prime way of taking care of patients. Genetic testing is still in its infancy. It doesn't help clinically in too many situations yet. It will in the future. It helps in the diagnosis, it's not as useful in the treatment. So we have a long ways to go with genetics. I like your comment that going forward we're going to need more genetic counselors to make sense of these results. Clinicians are going to have a hard time making sense of these results. I do think that there is plenty of role once a disease causing mutation has been defined, and in that situation it's invaluable in cascade screening in identifying other family members who may be affected, but outside that I do believe and I agree completely with both of you, that clinical medicine is not dead. And clinical evaluation should be number one and should enjoy it's prime time because that's where we still are at. And genetics is still in its infancy and so is cardiology. Dr Carolyn Lam: Perhaps in selective settings ... We're not talking here about, for example, hypercholesteremia variance, we're not talking about cancer gene variance for which screening may be a little bit more advanced, and we may understand the gene phenotype associations that are perhaps- Dr Mark Link: I think that understanding gene phenotype associations are going to be critically important in the future. I think, as Sanjay said, the real use of genetic screening now is cascade screening for the family, and there it's invaluable. That you can tell if you've got a co-band with the disease, and with a defined pathological mutation. You can test siblings, sons and daughters, parents to see if any of them have the gene. I think that's where it should be used for sure in 2018. Dr Carolyn Lam: Thank you so much Mark and Sanjay. So some precautions, some hope. Very, very balanced discussion. So much more we could discuss, so I really want to highly encourage our audience. Pick up this issue. You have to read these amazing papers and the editorials. Dr Carolyn Lam: So, here's a podcast with all your colleagues, and don't forget to tune in next week.
Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med. 2016 Feb 17
Dr. Carolyn Lam: Welcome to Circulation On The Run. Your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. In just a moment, we are going to be discussing the diagnostic conundrum of elevated high sensitivity cardiac troponin levels in a patient with renal disease, but also suspected of acute coronary syndrome. Aha! I bet I caught your attention. A very, very familiar diagnostic dilemma. So stay tuned right after these summaries. Cardiac allograft vasculopathy is the leading cause of death in patients more than five years post cardiac transplantation. It has been hypothesized that cardiac allograft vasculopathy results from interrupted lymphatic drainage post surgery. Since the donor lymphatic vessels are not inesthimozed to that of the recipient during transplantation, thus the lymphatic system may play a crucial role in the alloimmune response. Well, these hypothesis are addressed in the first paper in today's journal from first author Dr. Edwards, corresponding author Dr. Wong and colleagues from Kings College, London. These authors use spect CT lymphoscintigraphy in a pre-clinical model. And therefore provided objective quantification of lymphatic flow following transplantation and showed that this correlated to cardiac allograft vasculopathy. They demonstrated that cardiac lymphatic remodeling and lymphatic transport dysfunction post transplant was associated with cardiac allograft vasculopathy and transplant rejection. They further showed that lymphatic flow was increased during chronic rejection. This in turn may have resulted in enhanced trafficking of antigen presenting cells to the local draining lymph nodes in an augmented alloimmune response. Now although the cause and effect of this phenomenon could not be fully established, these data provided the impetus for the investigation of lymphangiogenesis inhibition as a means to dampen chronic rejection. The absorb bioresorbable vascular scaffold is known to completely resolve within three years after coronary artery implantation. However, what is the safety and effectiveness of these bioresorbable scaffolds during this critical three year period. First author Dr. Ali, corresponding author Dr. Stone and colleagues from Columbia University Medical Center performed an individual patient level meta analysis of the four randomized absorb trial and demonstrated that compared with metallic everolimus eluting stents, the bioresorbable vascular scaffold had higher rates of target lesion failure and device thrombosis cumulatively to three years and between one and three years. Multi-variable analysis identified the number of treated lesions, current tobacco use and previous cardiac interventions as independent predictors of three year target lesion failure. Whereas diabetes was predictive of three year device thrombosis in bioresorbable vascular scaffold treated patients. The next paper reported the three year follow up of the FAME 2 trial, which compared PCI guided bi-fractional flow reserve with best medical therapy in patients with stable coronary artery disease to assess clinical outcomes and cost effectiveness. First and corresponding author Dr. Fearon and colleagues from Stanford cardiovascular institute showed that major adverse cardiac events at three years were significantly lower in the PCI group, compared with the medical treatment group. This difference was primarily as a result of a lower rate of urgent revascularization. Mean initial costs were higher in the PCI group, but by three years, were similar between the two groups. The incremental cost effectiveness ratio for PCI compared to medical therapy was more than $17,000 per quality adjusted life year at two years and $1,600 per quality adjusted life year at three years. Thus the authors concluded that percutaneous coronary intervention in patients with stable coronary artery disease and at normal fractional flow reserve may be advantages compared to with medical therapy alone, because it results in improved clinical outcomes and quality of life at no increased cost by the end of three years follow up. The next study shows for the first time, that pioglitazone may prevent stroke as a single stand-alone outcome. Today's paper by first author Dr. Yaghi, corresponding author Dr. Kernan from Yale School of Medicine and colleagues was a secondary analysis of the iris trial, which showed that pioglitazone reduced the risk for a composite outcome of stroke on myocardial infarction among non-diabetic patients with insulin resistant and a recent stroke or transient ischemic attack. Now, the current planned secondary analysis used updated American Heart Association 2013 consensus criteria for ischemic stroke to examine the effect of pioglitazone on stroke outcomes. The study found that pioglitazone reduced the risk by 25% by five years, with absolute rates of 8% with pioglitazone versus 10.7% with placebo. Pioglitazone reduced the risk for ischemic strokes, but had no effect on the risk of hemorrhagic events. These findings add to the evidence that pioglitazone may be a potent therapy for vascular disease risk reduction and may help inform shared decision making by providers and patients for the use of pioglitazone after ischemic stroke or transient ischemic attack. Well, that ends it for our summaries. Now for a feature discussion. The cardiac troponins have really revolutionized cardiology. We use them in of course the diagnosis of myocardial infarction and in fact the recent European Society of Cardiology recommendations say that the rapid zero and one hour triage algorithm for rule in or rule out of non STEMI should use high sensitivity troponins and interestingly irrespective of renal function. Now this latter point has caused some confusion, some questions, since we all know that patients with chronic kidney disease frequently have higher or increased levels of cardiac troponins, especially since we now can detect them with the high sensitivity essays. And this is even in the absence of an acute coronary syndrome. Well, this week's journal contains two papers that address this topic so well. And I am delighted to have with us the corresponding author of the first paper, Dr. Christian Mueller from University Hospital Basel in Switzerland and the author of the second paper, Dr. Nicholas Mills from University of Edinburgh in Scotland. For the more, we have Dr. Torbjorn Omland, associate editor from University of Oslo in Norway. Lot's to talk about. Christian, could I start with you? Could you say in your own words the rationale for looking at this vulnerable population and then perhaps describe what you did in your study? Dr. Christian Mueller: I'm very thankful that Circulation shed a lot of light on the population of patients with renal dysfunction, because both as a clinician and as a researcher, I'm definitely convinced that they merit a lot of our attention for several reasons. So first, it's important to be aware that the incidents of acute myocardial infarction among patients presenting with acute chest pain is much higher in patients with renal dysfunction, as compared to patients with normal renal function. And second, atypical clinical presentations also are more frequent in patients with renal dysfunction. Then possibly third, the ECG of course also a mandatory tool in our assessment is more often showing unspecific signs that may mimic or obscure the presence of myocardial infarctions and most of them are related to left ventricular hypertrophy. And in addition, patients with renal dysfunction are more prone to adverse events, both related to cardiovascular medication. For example, anticoagulation as well as our cardiovascular procedures, including PCI. Now again, as both papers have a strong focus on troponin, also cardiac troponin is a bit more difficult to interpret in patients with renal dysfunction related to exactly as you mentioned chronic elevations of cardiac troponin, TNI related to chronic cardiovascular disease. And I think that's so important to stress, any troponin signal in a patient with renal dysfunction is real and should not be incorrectly attributed to just a problem of impaired secretion by the kidneys. Dr. Carolyn Lam: So definitely an even greater need to diagnose myocardial infarction accurately in this very high risk population. So tell us what you did. Dr. Christian Mueller: We assessed this challenging sub group within the APACE study. So APACE is a large international prospective diagnostic study that is run in five countries with 12 centers. And we actually enroll consecutive patients presenting with suspected myocardial infarction. And then all patients get a very detailed workup and then adjudicated final diagnosis. And the adjudicated file diagnosis is done by two independent cardiologists and is based on two enormous extensive sets of data. The clinical data set that has been obtained at the local site and of course includes cardiac imaging and standard troponin testing, ECG data. In the second set of data that includes the study specific data sets, including serial measurements with high sensitivity carry troponin essay and a lot of details characterization of patients and patient follow up. So this is the reference standard against which the one hour algorithm the European Society of Cardiology evaluated. And the one hour algorithm has been derived and previously validated in overall population. Mainly patients with normal renal function. And so we tried to evaluate the performance of this predefined algorithm specifically in patients with renal dysfunctions. So among a bit more than 3,000 patients, the prevalence of patients with renal dysfunction was 15%. So we had about 500 patients with renal dysfunction. And the interesting finding from our work is that first the prevalence of N-STEMI was nearly threefold in patients with renal dysfunction as compared to patients with normal renal function. And, fortunately the rule out part of the algorithm regarding sensitivity still works very well. It is, however, the efficacy of rule out that is lower in patients with renal dysfunction, simply because fewer patients really have very low troponin concentration and are therefore ineligible for rule out. However, as a clinician, the main concern with troponin and renal dysfunction is the rule in part, and specificity. And as you would think, specificity of the one hour algorithm was in fact significantly lower in patients with renal dysfunction. It was still appropriate for therapeutic consequences, but it was lower as compared to patients with normal renal function, so the specificity was 89% in patients with renal dysfunction, as compared to 96.5% in normal renal function. So the overall efficacy of the algorithm was lower in patients with renal dysfunction, however then when trying to create and derive optimized cut off levels, so all cut off levels optimized for use in renal dysfunction, we didn't really find alternative cut offs that would do a much better job than the official cut off levels recommended in the guidelines. So our conclusion is that in patients with renal dysfunction, the safety of the one hour algorithm still is very high, however the specificity of rule in and overall efficacy are decreased. Dr. Carolyn Lam: Right. That's beautifully summarized. And also that different cut offs didn't really help to increase the efficacy of this algorithm. And just to clarify to our listeners, I believe you defined renal dysfunction as an estimated GFR of less than 60, which is so beautiful because it's perfectly consistent with the second paper. Nick, could you please tell us about your study and your take home messages as well. Dr. Nicholas Mills: So high stakes is our clinical trial that we're conducting across hospitals in Scotland to evaluate the best way to use high levels of cardiac troponin in clinical practice. One of the areas of uncertainty is whether these assets really add any additional value for patients with chronic kidney disease, where troponin concentrations tend to be higher. And the premise of a high sensitive test is that we can measure lower concentrations and improve the sensitivity. But is this just going to create uncertainty for clinicians? So we evaluated 5,000 consecutive patients for performance of high sensitivity cardiac to put in testing. And those with and without renal impairment. And based upon what Christian, we identified that patients with renal impairment are less likely to have very low concentrations, but that you can rule out myocardial infarction safely in patients with renal impairment. And similarly that those with renal impairment are more likely to have an abnormal troponin concentration at presentation. Around about 40% of all patients have troponins above the upper reference limit. And whilst the specificity for myocardial infarction is lower, type one myocardial infarction or myocardial infarction due to plaque rupture or cardiac thrombosis remains the most common diagnosis in this group. Finally we looked at one year outcomes. And this is really critical. Because we found that patients with renal impairment were two to threefold more likely to die from cardiovascular disease one year following their presentation than those without renal impairment. And I think that my general experience during these tests in clinical practice is that troponin elevations in patients with kidney disease are often ignored and there's a concern about what they mean, and therefore these patients don't get access to the fantastic treatments we have for coronary heart disease. So our take home message is that high sets of troponin testing in patients with renal disease does have value, it's useful for identifying low risk patients although there are fewer of them, and it performs well as a diagnostic test, highlighting in particular a group of patients that really have poor clinical outcomes. As a cardiological community, we need to do better. Dr. Carolyn Lam: What I really love about both or your papers is the consistency in the messages. Torbjorn, I want to bring you in on this. You managed both papers. Such a lovely pair of papers that we're so proud to be publishing and you had also invited an editorial by Dr. deFilippi and Seliger. Would you like to comment on your perspective and perhaps the clinical take home message to our audience? Dr. Torbjørn Omland: Yes, I think this has been pointed very well out by both Christian and Nick. And I think it's worth recapitulating that renal dysfunction is a major problem that clinicians often try to explain by just lack of renal filtration. But that the closest probably are increased production and underlying cardiac disease. So in the editorial Dr. deFilippi Filippi and Dr. Seliger points also out in these things. Moreover they try to look forward and have made comments to recent studies that showed that in patients with renal dysfunction have different troponin fragments than patients with acute myocardial infarctions. Dr. Carolyn Lam: I find that so fascinating. And it really, really relates to the field of heart failure and what we are also talking and thinking about with natriuretic peptides and their different fragments and the possible different meanings. And how different essays maybe non specific for different fragments. Christian, you think a lot about these things. I'm curious, what are your thoughts on this and areas of future work that are very urgent? Dr. Christian Mueller: I think Torbjorn very nicely addressed this. So the current high sensitivity essays for T and I that we use in clinical practice, they are designed kind of to detect everything in blood that looks like troponin, either T or I, including various fragments. And I think it's a fantastic new avenue of research, trying to find out that the biochemical signatures can be further differentiated and exactly that perhaps different troponin fragments or tricordinate products more prominent in patients having ischemic injuries like treat myocardial infarction, as compared to for example other modes of injuries. So I think that's very nice hypothesis and some early data. But at least from my perspectives and to the best of my knowledge until now, the diagnostic algorithms that we have other ways to approach this in clinical practice. And so it's the higher the blood concentration in patients with acute chest pain, the more likely it's acute myocardial infarction. It's not any chronic disease and again the higher the change from presentation to one hour or two hours, the more likely it's acute as a dynamic disorder resulting in an acute increase in cardiac troponin, as compared to the chronic release patterns typically seen in patients with renal dysfunction. Dr. Carolyn Lam: Yeah. That's just so fascinating. Nick, we sadly are running out of time, but I do want to give you the last word. The clinical take home message, once again. What do you think listeners should take home that may change their practice, after listening to this podcast? Dr. Nicholas Mills: I think the key message for clinicians, is that in a patient with suspected acute coronary syndrome and has renal impairment and elevated troponin concentration, serial testing is mandatory to differentiate between those that have chronic myocardial injury due to subclinical heart disease and those that are having acute myocardial injury as a consequence of a presumed acute coronary syndrome. Field testing is critical to inform which treatment path and what investigations we recommend for our patients. Dr. Carolyn Lam: Wonderful. And to take any elevations seriously, because this is a high risk population. Well, audience you heard it right here on Circulation On The Run. I'm sure you've enjoyed this. I certainly have. Don't forget to tune in again next week.
Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carlolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore. What's the link between DPP4 and aortic valve calcification? Well, to find out, keep listening because we'll be discussing this and an important new paper right after these summaries. The first original paper in this issue tells us that high sensitivity Troponin I, may have a role in personalizing preventive strategies in patients with Type II Diabetes. Dr. Cavender and colleagues from University of North Carolina, Chapel Hill, sought to describe the relationship between changes in high sensitivity Troponin I and cardiovascular outcomes in the EXAMINE phase 3B trial, which was designed to evaluate the cardiovascular safety of alogliptin. The current analysis was restricted to patients, randomized 30 days or more after the qualifying acute coronary syndrome event, and high sensitivity Troponin I was measured using the Abbot Architect Assay at baseline and six months. The authors found that high sensitivity Troponin I was detectable in the vast majority - 93% of patients with Type II Diabetes, stabilized within 30 days after acute coronary syndrome. One in six of these patients had high sensitivity Troponin I levels above the 99th percentile upper reference limit. High sensitivity Troponin I had a strong graded relationship with the incidence of subsequent major cardiovascular events. Changes in high sensitivity Troponin I as small as two to six nanograms per liter over six months, were associated with a heightened risk of adverse outcomes. Particularly cardiovascular death and heart failure. Alogliptin neither increased nor decreased the risk of cardiovascular events in a high risk cohort of patients with elevated high sensitivity Troponin I levels. These findings therefore imply that serial measurements of high sensitivity Troponin may have a role in preventive strategies, either by intensifying or prolonging therapies in patients at high risk or reducing or shortening therapies in patients at low risk of cardiovascular events. The next paper describes the effects of Pioglitazone on cardiac outcomes after ischemic stroke or transient ischemic attack in patients with insulin resistance without diabetes in the IRIS trial, which stands for Insulin Resistance Intervention after Stroke. As a reminder, the IRIS trial compared the effects of Pioglitazone with placebo on major cardiovascular events after stroke or transient ischemic attack, in patients without diabetes but who had evidence of insulin resistance. And it showed that Pioglitazone improved insulin resistance, prevented diabetes, improved CRP and reduced fatal and non-fatal stroke or myocardial infarction. In the current paper, by Dr. Young and colleagues from Yale Cardiovascular Research Center in New Haven, Connecticut, the authors performed a secondary analysis of IRIS and examined the effect of Pioglitazone on acute coronary syndromes, mainly myocardial infarction or unstable angina. They found that Pioglitazone reduced the risk of these events by 29%, with benefit emerging after two years of treatment. Furthermore, Pioglitazone reduced the incidence of Type I myocardial infarction with a neutral effect on Type II myocardial infarction. In summary, among patients with insulin resistance without diabetes, Pioglitazone reduced the risk of acute coronary syndromes after a recent cerebrovascular event, and may serve as a useful secondary prevention therapy in addition to statins, aspirin, and other established treatments. The next study tells us that immune complexes may be an important biomarker in the risk stratification of Antiphospholipid Syndrome. Now recall that Antiphospholipid Syndrome is characterized by recurrent thrombosis in patients with Antiphospholipid predictive antibodies. However, the predictive value of the presence of Antiphospholipid auto antibodies is low. And new markers are needed to identify carriers at higher risk. In the current study by Dr. Serrano and colleagues from Madrid, Spain, the authors performed a historical cohort follow up study based on the Magnum 12 plus 12 cohort, that included all patients who had received a kidney transplant in their hospital in a 12 year period from 2000 to 2011. Sera used for the analysis were collected in the 24 hours before the kidney transplant surgery, and used to measure circulating immune complexes of immunoglobulin A bound to beta II glycoprotein I. The authors then investigated the possible association of these immune complexes with thrombosis, graft thrombosis and graft loss in the six months following kidney transplant. They found that in patients with the immunoglobulin A isotope antiphospholipid antibodies, the presence of circulating immune complexes of immunoglobulin A bound to beta II glycoprotein I, pre transplant, was associated with acute thrombotic events. Patients positive for the immune complexes had a much higher risk of developing post transplant thrombotic events, and higher risk of graft thrombosis mediated graft loss. On the other hand, complex negative patients had the same thrombosis risk as the control population. These findings imply that treatment to prevent thrombosis should focus mainly on the immune complex positive patients in this setting. The final paper addresses the issue that public reporting of PCI Outcomes may create disincentives for physicians to provide care for critically ill patients, particularly at institutions with worse clinical outcomes. In this study from first author, Dr. Waldo from the VA Eastern Colorado Health Care System in Denver, Colorado, corresponding author, Dr. Yeh from Beth Israel Deaconess Medical Center in Boston, Massachusetts, and colleagues. The authors used state reports to identify 31 out of 86 hospitals that were recognized as negative PCI outliers in two states: Massachusetts and New York, from 2002 to 2012. They sought to evaluate the procedural management and in hospital outcomes of patients treated for acute myocardial infarction before and after a hospital had been publicly identified as the negative outlier. They found that outlier facilities were larger, treating more acute myocardial infarction patients, and performed more PCI's than non outlier hospital. The rates of percutaneous revascularization increased similarly at outlier and non outlier institutions after report of the outlier status. After outlier designation, the in hospital mortality declined at the outlier institutions to a greater extent than was observed at the non outlier facilities. Thus, public reporting of outlier status may prompt outlier facilities to improve case selection, and employ systems improvements that optimize patient care, and improve in hospital mortality among patients with myocardial infarctions. We are going to have such a fun discussion in today's feature paper. Have you ever wondered what does dipeptidyl peptidase-4, or DPP4 have to do with aortic valve calcification? Well, you're about to learn, because in today's paper we actually learn that DPP4 inhibitors, which you might recognize from diabetes, you know drugs such as sitagliptin, could serve a potential therapeutic target in aortic valve disease. To tell us about it and discuss it, we have corresponding author, Dr. Jae-Kwan Song] from Asan Medical Center in Seoul, South Korea, as well as Dr. Thomas Eschenhagen, Associate Editor from University Hospital Hamburg Eppendorf in Germany. Welcome, gentlemen. Dr. Jae-Kwan Song: Hi. Dr. Thomas Eschenhagen: Hi. Dr. Carolyn Lam: Fascinating paper. I have to congratulate you first and foremost, but please tell us, what inspired you to look at DPP4 in aortic valve disease. Dr. Jae-Kwan Song: Yeah, actually as a clinician, I think there is two issues. One is the prevalence of calcific aortic valve disease is increasing rapidly in the developed and also developing countries. The second important issue is that we do not have effective medical treatment option. So I will say that the medical treatment of calcific aortic valve disease is a typical example of unmet clinical needs to serve this kind of troubled scientific issues, our team have focused on the reciprocal interaction between endothelial cells and interstitial cells. Because this potential mechanism was well reported by other investigators that the interaction between two cells are very critical for maintaining aortic valve tissues. So first we started with Enos knockout mouse, to go over what's going on in the aortic valve in the models. In the human tissues in patient with calcific aortic valve disease, we have found that DPP4 is specifically activated. That's the beginning of our study. Dr. Carolyn Lam: Could you please explain to those of us who don't do basic science research everyday, I mean, your study involves tissues both from humans and mirroring models. Could you explain it very simply what you did and what you found? Dr. Jae-Kwan Song: Yes, in the Enos Knockout mouse, we have found that those mouse showed very strong calcification process compared to the live animals. What is the mechanism of this enhanced calcification in this mouse? And we found that the loss of endothelial function is critical, and then we found that DPP4 is actively involved in the calcification process. The first test we have done is the isolation of developed interstitial cells. And then we focused on osteogenic transformation over this valvular interstitial cell both in the Enos Knockout mouse, and the human developing interstitial cells. So we have found that the endothelial dysfunction activates the DPP4 activity in these tissues, which resulted in the increase osteogenic transformation of developed interstitial cell. So that's the beginning of our observation. Dr. Carolyn Lam: And could you describe what you did subsequently to prove the whole mechanism? Dr. Jae-Kwan Song: As you know the DPP4 has many substrates including many peptides involved in glucose metabolism, so the hardest part of our study is what is the molecule target, or associated with DPP4 in the pathologic process of calcification in developing interstitial cells. We tested many different substrates known to the potential targets of DPP4, and we have found specifically insulin-like growth factor-1 (IGF-1) is the key proponent of all this process. With further study, we found that the DPP4 cleaves or inactivates or decrease IGF1 activity in the valvular interstitial cell, and in the normal status IGF1 is a very critical to protect osteoblastic transformation of valvular interstitial cell. We have found that the DP4 and IGF1 exercises key therapeutic target, and the key molecules involved in valvular calcification. As you know we do have a DP4 inhibitors, which were successfully clinically to reduce the diabetes control. So it's very easy to test the DP4 inhibitors in animal models. Both in the Enos Knockout mouse, and we also developed in the calcific aortic valve disease using some treatment, including Vitamin D and hypercholesterol and diet the in vivo experiment showed that [inaudible 00:13:58] inhibitors effectively prevented the development of calcification and prevented the development of calcification and prevented the developement of calcific aortic disease. This the main finding of our study. Dr. Carolyn Lam: That is so fascinating, and really especially what you just said, that sitagliptin in this rabbit model prevented calcific aortic valve disease with the concurrent increase in plasma IGF1 levels in line with the DPP4 inhibition. That is just such a beautiful piece of work, congratulations. And congratulations Thomas on managing such a nice paper. Take us under the hood about the discussions that happened with the editors. Surely you recognized the translational impact. What do you think? Is it time to reposition DPP4 inhibitors? Dr. Thomas Eschenhagen: We and the reviewers like the paper because first of all it describes a new, interesting biological mechanism. If we are done, and we like that it uses human samples, but also this treatment in two different animal models. This together, really makes it a strong paper, we've found perfectly suitable for Circulation. As you said Carolyn, the translation perspective is fascinating. Obviously it's very early days. There is no specific evidence yet from patients. But that could, in patients, take actually very very long. Even the big studies already been done with sitagliptin and other DPP4 inhibitors, that don't show a signal in this direction yet, but I would say that could still happen, and maybe in the long term, all of the cardiologists putting all this stuff in German it's call TAVS, in America it's called TAVR does not work anymore, obviously. That's just the speculation. But it gives a very interesting signal, and this study certainly should stimulate research in humans and do some prospective studies in patients. Dr. Carolyn Lam: Yes indeed. If I may ask, Jae-Kwan, do you have plans for further steps? Dr. Jae-Kwan Song: Yeah, we are expecting some [inaudible 00:16:06]. The first process with proof of concept study as you know is DP4 inhibitors have been actually been used for the diabetic controls, so we may have a patient cohort who also underwent [inaudible 00:16:22] echocardiogram [inaudible 00:16:23] while without medication. The analysis of those later can be used for proof of concept study. But we are challenging issues that although many drugs are classified as a DP4 inhibitors, we should really focus on the tissue distribution on these drugs, specifically on the cardiac issues. It may be possible that the different drugs have a different tissue distribution even after all our medication. The second critical issue is what is the actual dose of these drugs to prevent calcific aortic valve disease. Usually these drugs are used for diabetes control. We may need different lab results of these drugs for different critical indications. So that's the two important issues to be solved. Dr. Carolyn Lam: That's wonderfully put, and I couldn't agree more. Thomas, could we switch tracks a little bit. Because now that I have you online, and you're the first time joining us on the show too, tell us a little bit more about what it's like as an associate editor really looking at these pre clinical data, being able to parse out what you think has translational value, and especially for circulation. We have a very strong emphasis now on clinical translation. Share some of your thoughts there on how it's been for us. Dr. Thomas Eschenhagen: It's been a great experience. I do have some experience with other journals as an associate editor, or being on an editorial board. But I have to say circulation is really quite unique. I think it's a very strong group of people. I'm amazed by the level of knowledge and also the level of engagement of the other editors and associate editors, in every single paper. What's also really rewarding is the overall quality of papers being submitted to circulation, it's really great. A lot of papers are not only presenting some beautiful, basic science, but also this translational perspective, that's actually what we are looking for. So very solid, exciting scientific work in cells, animals, but always some link, either some materials from humans or a good link to a translation perspective. That's the perfect paper for circulation and I have to say we get quite a bit of them, and it's sometimes even difficult to pick the ones we really like. But it's great, it's really been a lot of fun. Dr. Carolyn Lam: This is actually one of the purposes of this podcast. It's hoping to share with our readers, with our listeners, what happens at these editor discussions because it's so interesting, I just wish everyone could listen to all the science and the clinical translation that we discuss. Thank you very much for sharing your thoughts today, both Thomas, and Jake Won, beautiful work. We're very proud to be publishing this work in circulation. Thank you listeners for joining us this week. Don't forget, tell all your friends about this podcast, and tune in again next week.
Background/Aims: Reduction of capillary network density occurs early in the development of metabolic syndrome and may be relevant for the precipitation of diabetes. Agonists of the peroxisome proliferator-activated receptor (PPAR)-gamma transcription factor are vasculoprotective, but their capacity for structural preservation of the microcirculation is unclear. Methods: Male Wistar rats were rendered diabetic by streptozotocin and treated with pioglitazone in chow for up to 12 weeks. Capillary density was determined in heart and skeletal muscle after platelet endothelial cell adhesion molecule-1 (PECAM-1) immunostaining. Hallmarks of apoptosis and angiogenesis were determined. Results: Capillary density deteriorated progressively in the presence of hyperglycemia (from 971/mm(2) to 475/mm(2) in quadriceps muscle during 13 weeks). Pioglitazone did not influence plasma glucose, left ventricular weight, or body weight but nearly doubled absolute and relative capillary densities compared to untreated controls (1.2 vs. 0.6 capillaries/myocyte in heart and 1.5 vs. 0.9 capillaries/myocyte in quadriceps muscle) after 13 weeks of diabetes. No antiapoptotic or angiogenic influence of pioglitazone was detected while a reduced expression of hypoxia-inducible factor-3 alpha and PPAR coactivator-1 alpha (PGC-1 alpha) mRNA as well as vascular endothelial growth factor (VEGF) protein possibly occurred as a consequence of improved vascularization. Conclusion: Pioglitazone preserves microvascular structure in diabetes independently of improvements in glycemic control and by a mechanism unrelated to VEGF-mediated angiogenesis. Copyright (C) 2012 S. Karger AG, Basel
Guest: Sunder Mudaliar, MD Host: Steven Edelman, MD How can we prevent and treat pre-diabetes? Can a pill delay or prevent the onset of disease in high-risk individuals? Host Dr. Steven Edelman talks to Dr. Sunder Mudaliar, clinical professor of medicine in the division of endocrinology and metabolsim at the VA Medical Center and University of California San Diego School of Medicine, about the data on pioglitazone for diabetes prevention and the results of the ACT NOW study.
Learn About the Causes and Rising Health Consequences of NASH; the Difference Between NASH and Fatty Liver Disease; and the Potential Benefit of Vitamin E Therapy Arun J. Sanyal, M.D., is professor of medicine and chairman, Division of Gastroenterology, at Virginia Commonwealth University Medical Center in Richmond, Virginia. After earning his undergraduate degrees from Patna University and Maulana Azad Medical College, both in India, Dr. Sanyal earned his doctor of medicine degree from the All India Institute of Medical Sciences in New Delhi. He completed a residency in internal medicine at the All India Institute of Medical Sciences, a residency in internal medicine at Texas Tech University Health Sciences Center in Amarillo, Texas, and a fellowship in gastroenterology and hepatology at VCU Medical Center, until being named professor of internal medicine, gastroenterology, hepatology and nutrition. Dr. Sanyal is the author of more than 80 articles in peer review medical journals including being co-author of a recent paper entitled:."Pioglitazone, Vitamin E, Or Placebo For Nonalcoholic Steatohepatitis," in the New England Journal of Medicine in May of 2010. Download or Open:
Hurst's the Heart Online Update
Background/Aims: We investigated the effect of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist pioglitazone on growth and TRAIL-induced apoptosis in carcinoid cells. Methods: Carcinoid cells were incubated without and with pioglitazone. Effects on growth were examined by cell count and cell cycle analysis. p21(waf1/cip1) expression was determined by Western blotting. Cytotoxicity assay was performed by FACS analysis. Results: Pioglitazone suppressed the growth and induced apoptosis of carcinoid cells. Additionally, pioglitazone significantly enhanced carcinoid cell death induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). The enhancement of TRAIL-induced apoptosis was associated with an upregulation of cyclin-dependent kinase inhibitor p21(waf1/cip1) in pioglitazone-treated carcinoid cells. Importantly, overexpression of p21(waf1/cip1) in carcinoid cells by adenoviral gene transfer of p21 sensitized them to TRAIL-induced apoptosis. Conclusions: These results suggest that pioglitazone inhibits cell growth and sensitizes cells to TRAIL-induced apoptosis by induction of p21(waf1/cip1). Therefore, pioglitazone can be an effective therapeutic adjuvant for the treatment of carcinoid tumors. Copyright (C) 2001 S. Karger AG, Basel.