Podcasts about Endothelin

In the final part of this series, Joseph Parambil, MD, walks us through the approach of managing pulmonary hypertension, reviews the pathophysiology and digs into the mechanisms and the differences in the medications. Intro 0:12 In this episode 0:17 Interview with Joseph Parambil, MD 2:53 Reviewing and clarifying pathophysiology prior to initiating therapeutics 4:13 Evaluating patients in terms of their functional status and how does that play a role in initiating therapies 4:25 Vasoreactivity testing 10:21 The categories of medications 14:40 Endothelin receptor antagonists 37:07 TGF pathway 42:13 Scleroderma patient and treatment 50:19 Do patients get a repeat right-heart catheterization? 55:51 What about the TGF-beta? 56:55 Thank you, Dr. Parambil 58:34 Thanks for listening 59:17 We'd love to hear from you! Send your comments/questions to Dr. Brown at rheuminationspodcast@healio.com. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum. Disclosures: Brown and Parambil report no relevant financial disclosures. Joseph Parambil, MD, is a staff member in the Respiratory Institute and the director of the HHT Center of Excellence and the Vascular Anomalies Center at the Cleveland Clinic. He is associate professor of medicine at Cleveland Clinic's Lerner College of Medicine. He is certified by the American Board of Internal Medicine with additional specialty certification in pulmonary medicine and critical care medicine.

Darshan H. Brahmbhatt, Podcast Editor of JACC: Advances, discusses a recently published original research paper on Increased Endothelin-1 Is Associated With Morbidity in Single Ventricle Heart Disease in Children Undergoing Fontan Palliation.

In this episode, we dive into the early therapies and how our understanding of vascular physiology drastically changed the management of pulmonary hypertension. Intro 0:12 In this episode 0:18 Recap of part 1 & 2 0:31 What part 3 is about 2:31 WHO conference in 1975: Treating pulmonary hypertension 3:48 The Discovery of Non-Steroidal Anti-inflammatory Drugs (NSAIDs), Part 1 5:20 Epoprostenol 6:18 Prostacyclin 10:37 Endothelin antagonists 11:41 Phosphodiesterase type 5 (PDE5) inhibitors 14:08 Interaction of nerves and blood vessels 15:06 The Soups VS the Sparks 17:36 A dreamed experiment 19:06 Acetylcholine 23:23  Enter “the calabar bean” 24:45 Acetylcholine and vasodilation: 1976 26:01 Rabbit aorta 27:45 Nitric oxide 29:38 Why are we using nitric oxide to treat pulmonary hypertension? 31:31 Tachyphylaxis 33:48 TNT factories 35:09 Nitrous oxide and tachyphylaxis 36:52 Pfizer in the 1980s 38:06 Understanding the trigger of pulmonary hypertension 40:53 PDE5 and nitric oxide and pulmonary hypertension 43:07 The end of the ripping yarns 44:20 Coming up in part 4 46:17 Thanks for listening 47:29 We'd love to hear from you! Send your comments/questions to Dr. Brown at rheuminationspodcast@healio.com. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum. References: Bernard C. C R Soc Biol. 1851;3:163-164. Furchgott RF, et al. Nature. 1980;doi:10.1038/288373a0. Galiè N, et al. N Engl J Med. 2005;doi:10.1056/NEJMoa050010. Ghofrani HA, et al. Nat Rev Drug Discov. 2006;doi:10.1038/nrd2030. Giordano D, et al. Biochim Biophys Acta. 2001;doi:10.1016/s0167-4889(01)00086-6. Guthrie F. Q J Chem Soc. 1859;doi:10.1039/QJ8591100245. Higenbottam T, et al. Lancet. 1984;doi:10.1016/s0140-6736(84)91452-1. Marsh N, et al. Clin Exp Pharmacol Physiol. 2000;doi:10.1046/j.1440-1681.2000.03240.x. Montastruc JL, et al. Clin Auton Res. 1996;doi:10.1007/BF02281906. Nejad SH, et al. Future Cardiol. 2024;doi:10.1080/14796678.2024.2367390. Tansey EM. C R Biol. 2006;doi:10.10116/j.crvi.2006.03.012. Warren JV. Trans Am Clin Climatol Assoc. 1988;99:10-6. Disclosures: Brown reports no relevant financial disclosures.

Guest: Donald Kohan, MD, PhD Increased formation of renal endothelin one is associated with renal injury.1 In several studies, activation of the ETA receptor has been shown to contribute to IgA nephropathy (IgAN) progression, and markers of endothelin system activity are elevated in patients with the disease.2,3-5 Join Dr Donald Kohan as he dives into the latest research on this connection, which could provide insight into new tailored therapy approaches for IgAN patients. Dr Kohan is a nephrologist at University of Utah Health in Salt Lake City. References: Kohan DE, Barton M. Kidney Int. 2014;86(5):896-904. doi:10.1038/ki.2014.143 Kohan DE et al. Kid Int Rep. 2023;8(11):2198-2210. doi:10.1016/j.ekir.2023.07.023 Lehrke I et al. J Am Soc Nephrol. 2001;12:2321-2329. doi.org/10.1681/ASN.v12112321 Zanatta CM et al. Ren Fail. 2012;34(3):308-315. doi:10.3109/0886022X.2011.647301 Tycova I et al. Physiol Res. 2018;67:93-105. doi.org/10.33549/physiolres.933670 FA-11319389 12/24

Nasal spray approved for chronic rhinosinusitis; Endothelin receptor antagonist gains approval to lower blood pressure in hypertension; One-time stem cell treatment approved for metachromatic leukodystrophy; NASH treatment gains accelerated approval; New automated insulin delivery system for type 1 diabetes.  

Commentary by Dr. Carmen Bergom

CME credits: 1.25 Valid until: 23-11-2023 Claim your CME credit at https://reachmd.com/programs/cme/sustained-blood-pressure-lowering-effect-with-the-dual-endothelin-receptor-antagonist-aprocitentan-in-resistant-hypertension-results-from-a-randomized-controlled-study-including-a-withdrawal-phase/14370/ In this program, expert faculty review and discuss real-world applications of the latest, practice-changing data across different therapeutic areas within cardiovascular medicine presented at the American Heart Association Scientific Session 2022.

The body's most potent vasoconstrictor? This season starts of on the topic endothelin, with an amazing interview with Professor David Pollock, former President of the American Physiological Society, from the University of Alabama at Birmingham.

CME credits: 1.00 Valid until: 15-08-2023 Claim your CME credit at https://reachmd.com/programs/cme/the-endothelin-et-system-and-its-role-in-resistant-hypertension/14225/ tbd

The Journal RETINA is devoted exclusively to diseases of the retina and vitreous. These podcasts are intended to bring to its listeners summaries of selected articles published in the current issue of this internationally acclaimed journal.

Is the loss of endothelin-B receptor mediated vasodilation in women after menopause due to aging or the decline in estradiol that occurs with menopause? Associate Editor Dr. Jason Carter (Montana State University) interviews senior author Megan Wenner (University of Delaware) and content expert Lacy Alexander (Pennsylvania State University) about the work by Wenner and co-authors to isolate and study specific effects of estradiol on the regulation of the ETB receptor. Shoemaker et al. enrolled young women in their study and utilized an endogenous hormone suppression with estradiol add-back experimental design to eliminate changes related to aging and other sex hormones. Wenner and collaborators then measured microvascular endothelial function using laser Doppler flowmetry while perfusing an antagonist for the ETB receptor via intradermal microdialysis fiber, a technique pioneered by Lacy Alexander. The authors found that when estradiol is present, the ETB receptor mediates vasodilation. However, when estradiol is absent or suppressed, ETB-mediated dilation is lost. Bottom line: changes in estradiol regulate the function of this ETB receptor. What is the clinical relevance of this work for women's health, in particular related to endometriosis, premature ovarian failure, and other pathophysiological conditions related to dysregulated sex hormones? Listen to learn more about this fascinating study and its implications on women's overall cardiovascular health.   Leena N. Shoemaker, Katherine M. Haigh, Andrew V. Kuczmarski, Shane J. McGinty, Laura M. Welti, Joshua C. Hobson, David G. Edwards, Ronald F. Feinberg, and Megan M. Wenner ETB receptor-mediated vasodilation is regulated by estradiol in young women Am J Physiol Heart Circ Physiol, published September 3, 2021. DOI: 10.1152/ajpheart.00087.2021

Claim free CME just for enjoying this episode! Disclosures: None Jump to: Patient summary - Case media - Case teaching - References CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Patient Summary- Syncope and Pulmonary Hypertension A Somali woman in her mid-30s with no significant past medical history presented with shortness of breath and exertional syncope. EKG revealed evidence of RV strain. CTA-PE protocol did not show PE. However, there was RV dilation and subsequent echocardiogram demonstrated normal LV, but moderately reduced RV function with evidence of RV pressure and volume overload. RVSP was estimated to be 188 mmHg! Case Media ABCDEFGHClick to Enlarge A. CXR, B. ECG, C. PA measurements: Main PA measures 2.4 cm, right PA measures 2.3 cm, left PA measures 1.9 cm, D. Tricuspid valve Doppler, E. RA tracing, F. RV tracing, G. PA tracing, H. Wedge tracing CTA PE: No PE, markedly dilated pulmonary trunk at 4.7 cm. Right main pulmonary artery measures 3.1 cm. TTE: Parasternal long axis: Moderate right ventricular dilation compressing left ventricle. Global right ventricular function is moderately reduced. TTE: Parasternal long axis- RV view: Right ventricular dilation with mild pulmonary regurgitation TTE: Mild pulmonary regurgitation with dilation of main PA TTE: Paradoxical septal motion consistent with right ventricular pressure and volume overload. TTE: Apical 4 chamberParadoxical septal motion consistent with right ventricular pressure and volume overload. Moderate right ventricular dilation.Global right ventricular function is moderately reduced.Severe right atrial enlargement. Paradoxical septal motion consistent with right ventricular pressure and volume overload.Moderate right ventricular dilation.Global right ventricular function is moderately reduced.Severe right atrial enlargement.Moderate to severe tricuspid regurgitation. TTE: Positive bubble study Episode Teaching Pearls Pulmonary hypertension (PH) can generally be categorized as pre-, post-, or combined pre- and post-capillary PH. Isolated pre-capillary pulmonary hypertension is characterized by: mean pulmonary artery pressure (mPAP) ≥ 20 mmHg, a pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, and a pulmonary vascular resistance (PVR) ≥ 3 Woods units (WU). Pulmonary arterial hypertension (PAH) (WHO Group 1) falls under pre-capillary pulmonary hypertension.Schistosomiasis is the most common cause of PAH (WHO Group I) worldwide. Approximately 7% of patient with hepatosplenic schistosomiasis have PAH. Some studies suggest that treatment of with praziquantel reverses vascular remodeling; however, there is point of no return, beyond which, anthelmintic therapies are ineffective to prevent progression.Exertional syncope and pericardial effusion are both risk factors for higher mortality in PAH.Women with severe PAH have extremely high risk of maternal morbidity and mortality. Endothelin receptor antagonists are contraindicated in pregnancy due to teratogenicity. Therefore, a pregnancy test must be obtained monthly while on this therapy.Patients with a lower socioeconomic status, based on median household income, have more advanced PAH at the time of diagnosis. Notes 1. How do you approach syncope? Syncope is a sudden transient loss of consciousness associated with absence of postural tone followed by complete and usually rapid recovery. There should be not be clinical evidence of “non-syncope” conditions including seizures, hypoglycemia, drug or alcohol intoxication, concussion due to head trauma and so forth. One approach to determining the etiology of the syncope is to consider 4 major categories: orthostatic, reflex-mediated, cardiac-obstructive,

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.03.367151v1?rss=1 Authors: Kodati, B., Stankowska, D. L., Krishnamoorthy, V. R., Krishnamoorthy, R. R. Abstract: Purpose: The goal of this study was to determine if JNK2 plays a causative role in endothelin-mediated loss of RGCs in mice. Methods: JNK2-/- and wild type (C57BL/6) mice were intravitreally injected in one eye with 1 nmole of ET-1, while the contralateral eye was injected with the vehicle. At two time points (2 h and 24 h) following the intravitreal injections, retinal sections were obtained and phosphorylated c-Jun was assessed. In a separate set of experiments, JNK2-/- and wild type mice were intravitreally injected with either 1 nmole of ET-1 or its vehicle, and euthanized 7 days post-injection. Retinal flat mounts were stained with antibodies to the RGC marker, Brn3a, and surviving RGCs were quantified. Axonal degeneration was assessed by imaging PPD stained optic nerve sections. Results: Intravitreal ET-1 administration produced a significant increase in immunostaining for phospho c-Jun in wild type mice, which was appreciably lower in the JNK2 -/- mice. A significant (p

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.27.357814v1?rss=1 Authors: Stankowska, D. L., Zhang, W., He, S., Krishnamoorthy, V. R., Harris, P., Hall, T., Chaphalkar, R. M., Kodati, B., Chavala, S. H., Krishnamoorthy, R. R. Abstract: Purpose: To determine if dietary administration of the dual ETA/ETB receptor antagonist, macitentan, could protect retinal ganglion cells (RGCs) following endothelin-1 (ET-1) mediated vasoconstriction in Brown Norway rats. Methods: Adult male and female Brown Norway rats were either untreated or treated with macitentan (5 mg/kg body weight) once a day for 3 days followed by intravitreal injection of either 4 l of 500 M ET-1 (2 nmole/eye) or vehicle in one eye. Imaging of the retinal vasculature using fluorescein angiography was carried out at various time points, including, 5, 10, 15, 25 and 30 minutes. Following the imaging of the vasculature, rats were either treated with macitentan (5 mg/kg/body weight in dietary gels) or untreated (control gels without medication). Following treatments, rats were euthanized, retinal flat mounts were prepared, immunostained for RGC marker Brn3a, imaged and surviving RGCs were counted in a masked manner. Results: Vasoconstrictive effects following intravitreal ET-1 injection were greatly reduced in rats administered with macitentan in the diet prior to the ET-1 administration. ET-1 intravitreal injection produced a 31% loss of RGCs which was significantly reduced in macitentan-treated rats. Following ET-1 administration, GFAP immunostaining was increased in the ganglion cell layer as well as in the retrolaminar region, suggestive of astrocytic activation by ET-1 administration. RGC numbers in macitentan treated and ET-1 injected rats were similar to that observed in control retinas. Conclusions: ET-1-mediated neurodegeneration could occur through both vascular and cellular mechanisms. The endothelin receptor antagonist, macitentan, has neuroprotective effects in retinas of Brown Norway rats that occurs through different mechanisms, including, enhancement of RGC survival and reduction ET-1 mediated vasoconstriction. Copy rights belong to original authors. Visit the link for more info

Pulmonary HypertensionSpecial Guest: Brian Murray, PharmD, BCCCP Reference List: https://pharmacytodose.files.wordpress.com/2020/09/ph-references.pdf 03:38 – Recent changes in PH management; 05:05 – PH classification; 10:22 – PH functional classification; 13:15 – PH diagnosis; 16:00 – Vasoreactivity challenge; 18:51 – Drug-induced PH; 21:08 – Short- and long-term PAH treatment goals; 23:50 – PH risk factors; 26:00 – Modifying outpatient PH medications/medication regimens; 33:03 – Fluid management in PH; 35:37 – VTE prophylaxis/treatment in PAH; 38:32 – Management of arrhythmias in PAH; 41:35 – CCB for PH treatment; 46:24 – Comparative studies in PH; 47:37 – Prostacyclins; 71:30 – Endothelin receptor antagonists; 76:04 – Phosphodiesterase inhibitors; 77:00 – sGC stimulator; 80:00 – Preferred treatment of PAH?; 84:53 – Vasopressors in patients with PH; 88:50 – Acute RV decompensation; 92:32 – Effect of positive pressure ventilation on PH; 94:55 – Management of outpatient PH infusion pumps; 97:22 – Take-home points PharmacyToDose.Com@PharmacyToDose on Twitter/InstagramPharmacyToDose@Gmail.com

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.07.138875v1?rss=1 Authors: Zambach, S. A., Cai, C., Helms, H. C. C., Hald, B. O., Fordsmann, J. C., Murmu Nielsen, R., Loenstrup, M., Brodin, B., Lauritzen, M. Abstract: Neurotransmitter-mediated signaling correlates strongly to changes in cerebral blood flow (CBF), and functional neuroimaging relies on the robust coupling between activity and CBF, i.e. neurovascular coupling (NVC). We here reveal that key endothelial signaling molecules, nitric oxide (eNO) and endothelin-1 (ET1), modulate pericyte contractility and that pericyte ATP-sensitive potassium (KATP) channels interact with endothelial factors to modulate vascular tone and NVC. We show that NVC requires local synthesis of cGMP, but not NO derived from endothelial cells. The potent endothelial vasoconstrictor ET1 contracted pericytes by IP3 receptor mediated Ca2+ release and blocked NVC. In comparison, pericyte KATP channel openers increased the diameter of capillaries by deactivation of L-type Ca2+ channels while KATP blockers shortened the NVC response. All vasoactive stimuli produced the largest diameter changes at the first capillary that branches off from the penetrating arteriole. Our results reveal that three different signaling pathways mediate the effects of NO, ET1 and KATP channels on brain pericytes and capillary blood flow by mechanisms similar to vascular smooth muscle despite great differences in morphology. Copy rights belong to original authors. Visit the link for more info

Dr. Sushrut S. Waikar discusses findings from the study, "Plasma Endothelin-1 and the Risk of Death and Hospitalization in End Stage Renal Disease Patients on Hemodialysis," on behalf of his co-authors.

Dr. Sushrut S. Waikar discusses findings from the study, "Plasma Endothelin-1 and the Risk of Death and Hospitalization in End Stage Renal Disease Patients on Hemodialysis," on behalf of his co-authors.

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 today's speaker paper is all about soy products and whether or not there is a benefit with them with regards to risk of coronary heart disease. Now, this has been extremely controversial and today's speech or paper is really important in its findings. Ha ha, I bet you want to get to it right now but I'm going to say, hold on let's get to some other really interesting papers in this series first. Can I start off? You got your coffee? Dr Greg Hundley: Yes. Let's get going Carolyn. Dr Carolyn Lam: So the first paper I want to highlight really talks about myocardial energetics in obesity, and you're going to love this one Greg it's got some really cool MRI techniques. We know that obesity is strongly associated with exercise intolerance and the development of heart failure particularly HFpEF. Well Dr Rayner from University of Oxford and colleagues looked at this carefully in 80 volunteers, which included 35 controls with an average BMI of 24 and 45 obese individuals with an average BMI of 35, who did not have coexisting cardiovascular disease. Now, these participants underwent body composition analysis and MRI of the abdominal liver and myocardial fat content, left ventricular function and 31 Phosphorus Magnetic Resonance Spectroscopy to assess Phosphocreatine ATP and Creatine Kinase Kinetics at rest and during Dobutamine Stress. Dr Greg Hundley: Oh, wow Carolyn, this is right up my alley. You've got MRI imaging for body composition coupled with MR spectroscopy for metabolism, so what did they find? Dr Carolyn Lam: Thanks for putting that simply for us Greg. They found that in the obese resting heart, the myocardial creatine kinase reaction rate is increase, maintaining ATP delivery despite reduced energy stores during increased workload. While the non obese heart increases ATP delivery through creatine kinase the obese heart does not, and this is associated with reduced systolic augmentation and exercise tolerance. Weight Loss reversed these energetic changes, so these findings really highlight myocardial energy delivery via creatine kinase as a potential therapeutic strategy to improve symptoms in obesity related heart disease, as well as a fascinating modifiable pathway involved in the progression to heart failure. Now with this paper the central illustration is so critical, everybody has to pick up that issue and have a look. Furthermore, you must read the elegant editorial by Barry Borlaug and Craig Malloy. Dr Greg Hundley: Oh, you bet Carolyn. Craig always puts these MR spectroscopy papers in such fantastic perspective, really looking forward to that read and such an elegant study. Now, we haven't had Carolyn's quiz in weeks and we're going to get into one. This paper comes from Professor Nina Wettschureck, from the Max-Planck-Institute for Heart and Lung research, and it pertains to the infamous G-protein coupled receptors. Now, Carolyn here's your quiz and guess what, it's just multiple choice. All you have to do is fill in the blank. Dr Carolyn Lam: On G-protein coupled receptors? Dr Greg Hundley: Yeah, I know it's... we know a lot about these, but we're going to learn. So, G-protein coupled receptors are the largest family of transmembrane receptors in eukaryotes. They transduce signals of numerous physio-chemical stimuli including... and Carolyn you have to complete this sentence. So it's neurotransmitters, hormones, local mediators, metabolic or olfactory cues and got to complete the sentence. Is it air resistance? Time? Or light? Dr Carolyn Lam: Space. Dr Greg Hundley: That's not a choice. Dr Carolyn Lam: All right, all right let me guess light. Dr Greg Hundley: That's awesome. Fantastic, great job Carolyn. So in the vascular system the contract alternative vessels is crucially regulated by these GPCRs, including basic constrictors such as Angiotensin two and Endothelin one. In this study the investigators studied the role of GPRC5B, and the regulation of contractility and differentiation in human and murine smooth muscle cells in vitro, as well as in tamoxifen inducible smooth muscle cells Pacific knockout mice under conditions of arterial hypertension and atherosclerosis, and these experiments were done in vivo. Dr Carolyn Lam: Okay, so what were the results? Dr Greg Hundley: They found that GPRC5B regulates vascular smooth muscle tone and differentiation by negatively regulating prostate cycling receptor signaling. Thus, Carolyn inhibition of the interaction between GPRC5B and the prostacyclin receptor might be beneficial in human arterial hypertension and vascular remodeling. What a great new insight into basic science. Well, let me get on I have a clinical paper, and this is on the infamous topic from the COMPASS-PCI trial, Rivaroxaban plus Aspirin versus Aspirin alone in patients with Prior Percutaneous Coronary Intervention from Dr Kevin Bainey at the Canadian VIGOUR Center in University of Alberta. So Carolyn, the cardiovascular outcomes for people using anticoagulation strategies or COMPASS trial demonstrated dual pathway intervention with Rivaroxaban 2.5 milligrams twice daily plus aspirin, and 100 milligrams once daily versus aspirin 100 milligrams once daily, reduced the primary major adverse cardiovascular event outcome of cardiovascular death, MI or stroke as well as mortality in patients with chronic coronary syndromes or peripheral arterial disease. Now, whether this remains true in patients with a history of PCI is unknown. Dr Carolyn Lam: Oh, Greg I'm so disappointed. Why didn't you give me a quiz here? I know about the COMPASS trial. Okay, so what did the author's find? Dr Greg Hundley: So Carolyn of the 27,000 plus patients in COMPASS 16,500 plus patients had chronic coronary syndrome, were randomized to DPI or aspirin and of these 9,862 had prior PCI. So here are the results, DPI compared with aspirin produce consistent reductions in MACE mortality, but with increased major bleeding with or without prior PCI. So among those with prior PCI one year and beyond, the effects on MACE and mortality were consistent irrespective of time since the last PCI. Dr Carolyn Lam: Mm-hmm (affirmative) Interesting implications on dual platelet inhibition. Well, let me tell you a little bit about what's in the mailbag in the rest of this issue. There's a research letter by Dr Joseph Wu on molecular signatures of beneficial class effects of statins on human induced pluripotent stem cell derived cardiomyocytes. We have global rounds by Dr Annika Rosengren and Dr Lars Wallentin on the cardiovascular medicine in Sweden. We have a White Paper by Dr Abhinav Saxena and colleagues on the value of hemodynamic monitoring in patients with cardiogenic shock undergoing mechanical circulatory support. And we also have paired perspective pieces, one by Dr Salim Virani and colleagues on secondary prevention of atherosclerotic cardiovascular disease comparing recent United States and European guidelines on dyslipidemia, and another by Dr Neil Stone and colleagues on comparing primary prevention recommendations with the focus look at the US versus European guidelines on dyslipidemia. Dr Greg Hundley: Very good, Carolyn. Well, I've got a research letter Professor Do-Young Kwon from the Korea University of Ansan Hospital, Korea University College of Medicine and discusses the association of Parkinson's disease with the risk of cardiovascular disease and all-cause mortality, and a nationwide population-based cohort study. In addition, different series of letters Dr Seung-Jung Park from Asan Medical Center at the University of Ulsan College of Medicine, and Professor Lang Li of The First Affiliated Hospital of Guangxi Medical University exchanged letters regarding the article, Clinically Significant Bleeding With Ticagrelor versus Clopidogrel in Korean patients with Acute Coronary Syndromes Intended for Invasive Management, that previously published randomized clinical trial. Then finally one of those great ECG investigations from Dr Miguel Arias, and they have an ECG quiz entitled The Hidden Reveals the Hidden, but really, it's referring to a Brugada ECG pattern and a patient with Wolff-Parkinson-White. I can't wait to get onto that feature article discussing the potential benefits or harms of soy in men and women as it relates to cardiovascular disease. Dr Carolyn Lam: Yeah, you and I Greg let's go. Oh, boy today's feature paper really literally cuts close to the heart for me talking about soy products, and whether or not there's a relationship with cardiovascular health. This remains controversial but thankfully we've got really great data just published in this week's issue, so proud to have the first author with us Dr Qi Sun from Brigham and Women's Hospital, as well as our associate editor who's also an editorialist for this paper and that's Dr Mercedes Carnethon from Northwestern University Feinberg School of Medicine. So welcome both I cannot wait to just jump right into it. Please, Qi, tell us what you found about soy products. Dr Qi Sun: First off this is a prospective cohort study that included three cohort studies, the Nurses’ Health Study and the Nurses’ Health Study II and Health Professionals Follow-Up Study. So those three big prospective cohort follow up studies. Now over the years we have collected much data of diet which has been repeated, reviewed, and assessed over the years, and we have accumulated many cases of cardinal heart disease the numbers are a solid. Now what we found is that the intake isoflavones which are the big family are flavonoids, the higher intake of isoflavones were associated with a lower risk of developing coronary heart disease in those three cohorts of men and women. And in addition because tofu and soy milk are the primary contributor in our guide of isoflavones, we also examine the tofu and soy milk in relation to the risk of cardinal heart disease What we found is that tofu intake is significantly associated with lower risk of developing heart disease, and soy milk is also associated with lower risk of developing heart disease. It's just the association for soy milk, soy milk is not significant. And I think very interestingly we also found that the menopausal status and the postmenopausal hormone use somewhat also modulated association primarily for coffee intake with heart disease risk, in that we found younger women who were before their menopause and also postmenopausal women who did not use hormone will benefit more from tofu intake. In contrast, for postmenopausal women who are using hormone the association was not significant. I think those are the primary findings of our prospective cohort study. Dr Carolyn Lam: Oh my goodness, hallelujah. That's really marvelous and beautifully summarized, Mercedes please explain why was this such a controversial area before? And what does this paper add? Love your editorial by the way. Mercedes Carnethon: We hear a lot about nutritional epidemiology studies, and we have a lot of debates about what we should believe, whether we should change our behavior based on these observational studies and quite often we have discussions about what's new. And I lean on that final point about why I like this particular paper so much, and that's because I found the topic of isoflavones, tofu intake and soy to be extremely relevant to a large proportion of the world's population, whose primary protein intake may be something made from a soybean, heavy and isoflavones. Within the United States it's also relevant even though a smaller proportion of our population relies primarily on vegetarian diet, there is a very large and interested group wondering whether soy intake is safe. There have been discussions about whether there's harm associated with it, and the possibility that it could have beneficial influence on our leading causes of death of coronary heart disease. So I was most thrilled about the innovation of this particular topic, and its methodological rigor. When we think about what we lean on, we lean on large studies, we lean on multiple events and the size of the study allowed the investigators to explore numerous subtleties. Subtleties such as that reported related to the moderation by menopausal status, and that was the point I was most curious about and why I'm really excited to have an opportunity to talk to you today Chi. Can you tell me a little more about the menopausal status finding? Dr Qi Sun: So first off as I mentioned tofu intake was more strongly associated with lower risk of developing heart disease among younger pre-menopausal women, or postmenopausal women who did not use ham. Before that I want to also mention for isoflavones intake where I also found a similar pattern in that isoflavones are more. Appear to be more strongly associated with lower risk also in those two groups of women, although the past by interaction was non-significant. Now in terms of why I think there are a couple reasons why is that, among postmenopausal female or in our use hormone, the isoflavone can function as estrogen and provide at least partially the estrogenic effects that were calculated in postmenopausal women who do not use hormone, and for premenopausal women we think that's probably because before menopausal, the activity of estrogen receptor may be higher than the estrogen receptor after menopausal. So, in reality, the other variables of isoflavones may provide estrogen effects after menopausal. So those are the hypotheses although I have to mention that those hypotheses, we need more evidence to really shed light on the mechanisms underlying those interactions between menopausal status, postmenopausal hormonal use, where's the intake of isoflavones and tofu. Dr Carolyn Lam: So Chi I love that explanation and giving it some biological possibility, although as you said it's a postulation. But may I ask so what's the implication for men? I lived with a man who thinks if he takes soy he's going to grow boobs. So what... did you see any sex differences and do studies like this and able looking for the downsides of eating soy? Dr Qi Sun: As a scientist I'm open to any kind of new findings as long as the findings are from well conducted, rigorously designed study. But having said that I couldn't exclude the possibility that maybe soy intake is associated with certain adverse health outcomes, but so far based on my experience I didn't see any such evidence. But having said this I always say I wouldn't risk any possibility, but coming... circling back to the coronary heart disease we really didn't see much difference between men and women. It's true for the younger women we saw a stronger association but for men I also see a lower risk of heart disease. So there's a kind of interesting image on soy intake or isoflavones intake in the United States that people believe they are estrogen so a man shouldn't take it, but if you look at the group of vegetarians, the vegans. There are a lot of guys they practice vegetarian, they practice vegan diets and we also publish on plant-based diet in relation to coronary heart disease and lot of men eat very healthy. And we found those people who practice those kinds of healthy diets, soy is often mouthful of primary sources of proteins and if you look at their risk of developing heart disease, type two diabetes is quite low. Something lower than other normal women who practice otherwise omnivore diet. Dr Carolyn Lam: It's true Qi soy intake could also be a marker of a healthier lifestyle in general, by extension of what you just said. But Mercedes I love that you discuss quite a number of these issues in your editorial and at the end of the day you asked the most important question, what does this mean for us? Should we all be increasing our intake of soy products? Could you give us your synthesis of that? Mercedes Carnethon: Yes, a point that I've definitely tried to make here, and this is really in response to what I expect to be the media fear surrounding new dietary findings. One of the first questions that I know that she and his colleagues will be asked is, should I change my diet? Can I extend my life? And that's because the media is really looking for a lot of sensational headlines in this topic, and I think we have to focus on what we learn from these observational studies. They're a very important step in the scientific process that helps us provide a justification for later clinical trials, that helps us think about the multiple components that work together to promote overall excellent health. And the point you were making right before this about the individuals who eat plant based diets that are heavily based in soy. In the paper it also describes that those individuals exercise more, they may have lower intakes of saturated fat, and so I think ultimately what I take from this at least for myself and for people who would ask is that an overall healthy diet seems to stand up very well in these well done observational studies. And that soy in particular may be a part of an overall healthy diet given what we're seeing here in this very well done study. Dr Carolyn Lam: Oh, that's beautifully put Mercedes and Chi perhaps I can give you the last word. What would you say is the take home message and what are next steps? Dr Qi Sun: I think the core message is this as Mercedes very well discussed, I think soy and especially tofu can be really good components of the overall healthy plant based diet, and by practicing that I think we can significantly reduce the risk of developing coronary heart disease for both men and the women. I think moving forward we would like to see evidence from clinical trials that target cardiometabolic risk factors as outcome, and to see whether increased consumption of tofu and isoflavones can really reduce those risk markers so that they have ample evidence to support the mechanisms. As you mentioned Carolyn that this is an initial study, and it could be soy, intake could be just macro how is it, through clinical trials, we can really control those confounding factors and really provide good evidence to support our findings. Dr Carolyn Lam: Well, in the meantime I just have to say you made my day this is coming from a soy eating vegetarian, so thank you so, so much. Thank you, listeners for joining us today. Dr Greg Hundley: This program is copyright the American Heart Association 2020.  

Cast:Joel TopfJennie LinSamira FaroukSwapnil HiremathShow Notes:NephJC coverage of SONAR: http://www.nephjc.com/news/sonarSONAR in PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30995972Avosentan for overt diabetic nephropathy, the ASCEND trial: https://www.ncbi.nlm.nih.gov/pubmed/20167702RADAR coverage at NephJC, May 2014: http://www.nephjc.com/atrasentanRADAR in PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24722445/Google Hangout on RADAR: https://www.youtube.com/watch?v=pkkQbb-isog&feature=youtu.beVlado Perkovic: https://twitter.com/VladoPerkovicSONAR: https://en.wikipedia.org/wiki/SonarNephmadness adaptive trial: https://ajkdblog.org/2016/03/10/nephmadness-2016-statistics-in-nephrology-region/#adaptiveKIDNEYcon adaptive trial tweet thread: https://twitter.com/hswapnil/status/1117194018331471873?s=21Excellent NEJM review on adaptive trials: https://www.nejm.org/doi/10.1056/NEJMra1510061Potential role of Adaptive trials in AKI: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869991/BNP levels in CKD: https://cjasn.asnjournals.org/content/3/6/1644Generalizability from Wikipedia: https://en.wikipedia.org/wiki/Generalizability_theoryAnemia (and other adverse effects) of Endothelin antagonists: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210319/Data safety monitoring boards: https://www.nidcr.nih.gov/research/human-subjects-research/interventional-studies/data-and-safety-monitoring-board-guidelinesAbbVie Allergen Merger: https://www.barrons.com/articles/abbvie-allergan-merger-pharma-deals-takeda-celgene-bristol-myers-squibb-51563890831Tangri Kidney Failure Risk Equation: https://qxmd.com/calculate/calculator_308/kidney-failure-risk-equation-4-variableFragility index paper: https://www.ncbi.nlm.nih.gov/m/pubmed/24508144/LITFL write up: https://litfl.com/fragility-index/Calculator: https://clincalc.com/Stats/FragilityIndex.aspxCANVAS Trial: https://www.nejm.org/doi/full/10.1056/NEJMoa1811744Rates of Hyperkalemia after Publication of the Randomized Aldactone Evaluation Study by David Juurlink et al.: https://www.nejm.org/doi/full/10.1056/NEJMoa040135Vinay Prasad: https://en.wikipedia.org/wiki/Vinay_PrasadClassic mouse studies looking at endothelin: https://www.jci.org/articles/view/119297/pdfhttps://www.ncbi.nlm.nih.gov/pubmed/8377387/https://diabetes.diabetesjournals.org/content/65/8/2429Nice reviews:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698004/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4216619/Review of vascular effects:https://www.ncbi.nlm.nih.gov/pubmed/28223322

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, Associate Editor of Circulation and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article is going to focus on trastuzumab-induced cardiac dysfunction in breast cancer patients. We will discuss with Stanford investigators their use of pluripotent stem cells that are differentiated to cardiomyocytes and subsequently exposed to toxins to determine an individual's susceptibility to cardio-toxicity from cancer treatment. But before we get to that, Carolyn, do you have a paper that you'd like to discuss? Dr Carolyn Lam:                Well, the first paper deals with cardiac biomarkers and asks the questions, can these biomarkers be useful for the diagnosis and risk stratification of syncope?" Now, this paper is from Dr Mueller and colleagues from University of Hospital Basel in Switzerland. They evaluated the diagnostic and prognostic accuracy of BNP, NT-proBNP, high-sensitivity cardiac troponin T, and high-sensitivity cardiac troponin I concentrations, alone and against the ones of clinical assessments in more than 1,500 patients presented with syncope to the emergency department in a prospective, diagnostic multi-center study. Now, cardiac syncope was adjudicated in 234 or 15% of patients. What they found was that the diagnostic accuracy from cardiac syncope, as quantified by the area under curve, was 0.77 to 0.78 for all four biomarkers. That was superior to that of the syncope-specific diagnostic score, EGSYS.                                                 Now, combining the four biomarkers further improved diagnostic accuracy to an area under curve of 0.81. Furthermore, using the four biomarkers at cutoffs achieved predefined thresholds for sensitivity and specificity and allowed rule-in or rule-out of 30% of all patients. Finally, the biomarkers predicted adverse cardiac outcomes with moderate to good prognostic accuracy and better than some of the existing syncope risk-prediction scores. Dr Greg Hundley:             Very interesting, Carolyn. Do you think we can now use this clinically? Should we be drawing these biomarkers on patients with syncope? Dr Carolyn Lam:                These results really do imply that these biomarkers look like useful tools for the early rule-out and/or rule-in of cardiac syncope in the emergency department. After all, these biomarkers are readily available, inexpensive, and results of this study suggest that they have potential to simplify diagnosis and to risk stratify in challenging presentations. However, before embracing the concept of ordering cardiac biomarkers routinely for syncope presentation, we really need to read the editorial by Dr Sandhu and Sheldon, in which important perspectives are presented, such as considerations of the certainty of the diagnosis of syncope, the usefulness of the comparative scores, the timing of testing, the potential unintended adverse consequences of testing. These editorialists concluded that, although promising, further work is needed to determine how the use of cardiac biomarkers should be incorporated into a risk-stratification algorithm. Dr Greg Hundley:             Wow, Carolyn. It sounds like we'd get a lot out of that particular editorial. I'm going to switch over and talk about NT-proBNP in patients with pulmonary hypertension. This is a paper from Dr Kelly Chin from UT Southwestern, and the study evaluated the utility of end terminal pro BNP level thresholds and assessing prognosis in pulmonary hypotension using the GRIPHON study. So GRIPHON is a global double blind, randomized placebo control event driven phase 3 study which assesses the safety and efficacy or a Prostacyclin agonist that promotes pulmonary arterial vasodilation.                                                 They performed the study in patients that were 18 to 75 years old with a diagnosis of idiopathic pulmonary hypertension, heritable hypertension or pulmonary hypertension associated with connective tissue disease, repaired congenital systemic pulmonary shunts, HIV infection, drug use or toxin exposure; and the diagnosis of pulmonary hypertension was confirmed by right heart catheterization and by a reduced 6-minute walk distance of 50 to 450 meters.                                                 Eligible patients were permitted to take their other therapies including Endothelin receptor agonists and phosphodiesterase type-5 inhibitors. The patients were categorized into low, medium and high in terminal BNP level subgroups according to two thresholds. First, by just the tertiles within the study overall and the secondly by the ESC guideline cutoff ranges. Dr Carolyn Lam:                Nice, so what did they find Greg? Dr Greg Hundley:             Well first of all both thresholds either the tertile one of the ESC in follow-up NT-proBNP categories were highly prognostic for future morbidity and mortality. And their time dependent analysis the risk of experience a morbidity or mortality even was 92% and 83% lower in the treated patients with a low and medium NT Pro BNP level. And 90% and 56% lower in placebo treated patients with low and medium NT-proBNP levels. So both, whether you're taking that drug of not, the NT-proBNP levels were prognostically valuable. More pronounced treatment benefit of selexipag was seen in the medium and low proBNP groups. There was a positive value for the interaction term. Dr Carolyn Lam:                Wow, sounds like two really important findings. Dr Greg Hundley:             Yes, exactly Carolyn. So first, NT-proBNP levels are highly prognostic for pulmonary arterial hypertension progression. And having NT-proBNP in the low range, by improving to or maintaining low NT-proBNP levels is a clinically relevant treatment goal for those with pulmonary artery hypertension. And of course as we described this was a very diverse well represented group of many different types of patients with pulmonary hypertension. Then second, while selexipag the study drug was beneficial in all NT-proBNP categories, the treatment effect was greater in those with low and medium categories versus the very high. Suggesting that earlier selexipag treatment may be of greater benefit. But very interesting biomarker study that follows up on yours Carolyn. Dr Carolyn Lam:                Indeed! Dr Greg Hundley:             Carolyn what about your next paper? Dr Carolyn Lam:                Well I want to switch tracks now and talk about iron. And the question is, how does intravenous iron repletion augment exercise capacity in chronic heart failure? Even if hemoglobin doesn't change. So, first some background right, now, besides hemoglobin it's important to recognize that iron is an obligate component of the mitochondrial enzymes that generate cellular energy in the form of adenosine triphosphate and phosphocreatine. So dynamic phosphorous magnetic resonance spectroscopy is a noninvasive tool that can really quantify the in vivo muscle energetics by measuring the kinetics of phosphocreatine recovery after exertion. These authors use this technique, and these are Dr Okonko from King's College, London British Heart Foundation sender of excellence, school of cardiovascular medicine and sciences. The James Black Center in London and colleagues. And what they did was they tested the hypothesis that intravenous iron repletion in chronic heart failure would enhance skeletal muscle energetics as reflected by a shorter phosphocreatine recovery halftime on phosphorous magnetic resonance spectroscopy imagining of the skeletal muscles. And they looked at 40 patients with chronic heart failure with reduced deduction and iron deficiency in a randomized double blind placebo controlled ferric iron and heart failure trial. Dr Greg Hundley:             So, what did they find? Dr Carolyn Lam:                They found that a single total dose infusion of intravenous iron repleted iron stores and augmented skeletal muscle energetics at 2 weeks post infusion. Enhancements in the skeletal muscle energetics which implied better mitochondrial function were accompanies by improved symptoms despite no change in hemoglobin at 2 weeks. So, this trial really provides mechanistic support for iron repletion in patients with chronic heart failure and its very importantly discussed in an editorial by Peter van der Meer, Haye van der Wal, and Vojtech Melenovsky. And I really suggest that everybody read that. Dr Greg Hundley:             Well, I'm going to talk a little bit about dietary omega-6 fatty acids and the incidence of cardiovascular disease and mortality. And this paper is from Matti Marklund from the Georgia Institute for Global Health and the University of New South Wales in Sydney, Australia. The study focuses on linoleic acid which is an omega-6 polyunsaturated fatty acid that we get from pumpkin seeds, flax seeds, walnuts, soybean oil, canola oil and grapeseed. It's been associated with a decrease in cardiovascular risk, but others have worried about an effect of consumption mainly the downstream production of arachidonic acid which can give rise to eicosanoids that are both pro inflammatory and pro thrombotic.                                                 And it's interesting Carolyn, several organizations suggest replacing saturated fat and carbohydrates with linoleic acid. So this study was really performed to address whether consumption of linoleic acid is associated with future cardiovascular events. In the study, investigators measured linoleic acid as well as arachidonic acid levels and from a global consortium across 30 perspective observational studies from 13 countries they performed multi variable adjusted associations of circulating an adipose tissue linoleic and arachidonic acid biomarkers with incident total cardiovascular disease and subtypes of cardiovascular disease including, coronary heart disease, ischemic stroke and cardiovascular mortality and this was all done as pre-specified analytic plan. Dr Carolyn Lam:                Wow, so what did they find? Dr Greg Hundley:             Well did I put you to sleep discussing all of that? Dr Carolyn Lam:                No! You have to tell me what they found. I'm seriously so interested in this topic because being vegetarian I actually get my source of omega fatty acids exactly from these sources. Dr Greg Hundley:             Okay, so Carolyn, higher levels of linoleic acid were associated with lower risk of total cardiovascular disease, ischemic stroke, cardiovascular mortality. While arachidonic acid was not associated with cardiovascular risks. And so, the clinical implications of the results support the potential benefits of main dietary omega- 6 fatty acid. That is linoleic acid for cardiovascular disease prevention. Now, while the trial is not randomized so we don't have definitive answers, the results do not support any theorized cardiovascular harms of consuming omega-6 fatty acids. And there is an excellent review on polyunsaturated versus saturated fat intake by Thomas Sanders from King's College, London as an editorial to this piece. So Carolyn I think we're safe right now in consuming linoleic acid. So how about a transition to our featured article and learn a little bit more about trastuzumab-induced cardiac dysfunction. Dr Carolyn Lam:                Absolutely! Dr Greg Hundley:             Great.                                                 Welcome everybody, we have a fantastic paper to discuss. We're going to review human induced pluripotent stem cell derived cardiomyocytes and how they can be used to identify individuals at risk of trastuzumab-induced cardiac dysfunction after treatment for breast cancer. We have today Nazish Sayed and also Dr Joseph Wu, both from Stanford University in California.                                                 Welcome gentlemen. Dr Joseph Wu:                   Thank you for inviting us. Dr Nazish Sayed:              Thank you. Dr Greg Hundley:             Nazish tell us a little bit about what are these human induced pluripotent stem cells and then also describe your experiment and what were your results? Dr Nazish Sayed:              So, induced pluripotent stem cells is about 10 years ago I knew technology where you can actually turn back the clock by you taking human fiber blast or blood cells and then you can test full reprogramming factors and turn back differentiated cells to pluripotent stem cells will mimic like catalytic stem cells. The catalytics include self-renewal, pluripotency and the most important that they can be differentiated to any cell type in the body. For example, cardiomyocytes or endothelial cells the neuron and kind of mimic these differentiated cells from the same individual from where the IPSCs were derived from.                                                 So, what we did in our study is we used this platform to derive these pluripotent stem cells from patients and then differentiated them into a cardiomyocyte to understand what would these human cardiomyocytes behave in a dish when treated with a Herceptin or trastuzumab and then kind of determine the underlying mechanism for this cardiac dysfunction. It seemed really difficult to model trastuzumab and use cardiac dysfunction as a heart which is the receptor for the trastuzumab is expressed only in humans.                                                 People have usually relied on animal model and for the first time what we did is we used these ideas of cardiomyocytes to model this dysfunction in a dish. Our results were pretty straightforward. We found that the IPSCs cardiomyocytes when treated with the chemotherapy agent showed cardiac dysfunction in the case of decrease contractility. The contraction velocity of these each individual cardiomyocytes is significantly reduced. More with this was also confirmed by having impaired calcium cycling which is very important for the contractility of these cardiomyocytes.                                                 But I think the most important thing which we determined from the study is that individuals who are treated with trastuzumab have a metabolic impairment in these cardiomyocytes which is convenient but however have a severe impact on this contractility and calcium handling in these cardiomyocytes. And that was one of the gist of these papers to figure out the metabolic impairment could be a target where we can improve this cardiac dysfunction in these patients. Dr Greg Hundley:             And so, after you discovered this, I noticed you also did some work with AMPK activators and perhaps would reverse some of the dysfunction. Could you describe a little bit what are AMPK activators and then how did they reverse the dysfunction that you observed? Dr Nazish Sayed:              In our study we characterized these IPS cardiomyocytes from these individuals and then we ran a whole sequencing of them after treatment where trastuzumab to see which of the pathways which could be down regulated or dysfunction when compared to the control patients which are not treated with trastuzumab. And one of the most significant pathways which we found was in PK pathways which was down regulated in the trastuzumab treated IPSC cardiomyocytes. So knowing that the AMPK activators are used for metabolic diseases, for example being diabetes and metabolic dysfunction, we thought that this same thing could be used in a dish where we can take these AMPK activators and simultaneously cotreat cardiomyocytes with Herceptin or trastuzumab to see if we can rescue the phenotype and indeed you can see in our paper we used 4 different AMPK activators with metformin which is a commonly used diabetic drug. Showing the best rescue for that trastuzumab induced cardiac dysfunction. Dr Greg Hundley:             Very intriguing because it looks like you've been able to harvest cells from individuals and then pre-treat them, understand the mechanism of dysfunction, understand who's at risk of dysfunction and then offer therapeutic interventions to perhaps prevent that dysfunction in this patient population. Joe, turning to you now, this is really revolutionary technology it seems to me. Can you describe how long does this process take? Is this something that we see might come into clinical medicine soon? Dr Joseph Wu:                   We're really excited about this technology that Nazish has described. I think as you know we've been working on this platform for the past 10+ years. In terms of the timeline, right now it takes us about a month to generate the induced pluripotent stem cells. It takes us another month to expand, propagate the IP itself. It takes us another month to generate the IPS cardiomyocytes. And it will take us probably another month to do all the phenotypic characterization in terms of using these IPS cardiomyocytes to expose them to various chemotherapy drugs and see how the chemotherapy drugs have an effect on these cardiomyocytes.                                                 So, I would say the total timeline is 12 months at this moment. Is it possible that the timeline could be crunched, could be shrunk over time? Yes that's possible, I think the technology is improving month by month, week by week because there are many different labs trying to work on this platform trying to improve the whole process. But right now one of the limitations that as you pointed out is this 4 month time period. And also the cost that's associated with this. But we're hopeful that over time that both the time, the costs can go down so that we can offer this type of platform to help patients diagnosed with cancer, find out what kind of chemotherapy is safe to use, what kind of chemotherapy is not safe to use. Dr Greg Hundley:             So, we're working towards clinical applications but at this point in time it looks like a fantastic platform for understanding, diagnoses and understanding pathways that for patients particularly as they are treated for cancer will experience cardiovascular dysfunction. So, switching a little bit and asking a related question. Patients that receive trastuzumab often also receive doxorubicin. Especially the breast cancer patients. If you looked at this technology trying to understand, and certainly those more at risk for trastuzumab associated left ventricular dysfunction, are the patients that previously received doxorubicin. Have you and your group looked at patients that have also received doxorubicin and then went on to receive trastuzumab relative to those that received trastuzumab alone? Dr Joseph Wu:                   I think for these two populations for this particular study, we tried to keep them clean. Meaning that we're looking mostly for trastuzumab treated patients, otherwise it's hard for us to piece out whether the toxicity was due to one medication or the other medication. But what you are asking is very important because as you pointed out many of these patients received both and I think for future studies we should be able to model both medications, meaning that take some IPS cardiomyocytes treated with doxorubicin, treated with Herceptin by itself and treated with both the medications.                                                 In previous studies we have studied using IPS cardiomyocytes the effects of doxorubicin induced cardiac toxicity. In just the assessment, doxorubicin is a very common effective chemotherapy for breast cancer medications and just like Herceptin, the clinicians struggled with the issue, as we cannot predict which patient will develop toxicity. And then granted the doxorubicin induced toxicity has a slight different mechanism compared to perception induced mild cardiac dysfunction that this Nazish had mentioned about. But these are kind of the studies that we're very excited because now for the first time we have a way to model this. Otherwise they alternative would be not possible, for example it would not be possible for us to biopsy breast cancer patients woman's heart to study the cells.                                                 Especially in the case of perception. The receptor that's being studied is not present in animal model cells. For example not present in mouse cardiomyocytes and therefore it would be very difficult to understand the mechanism and this is the reason why the patient specific and disease specific IPS cardiomyocytes become so useful. Dr Greg Hundley:             Do you find another emerging therapy in this entire realm is the immunotherapies? Do you think this technology will be applied to determine susceptibility to immune mediated toxicity? Dr Joseph Wu:                   This is a very good question as well Greg. We've been thinking about studying that and as you know, it's a more complicated system because it involves patients’ immune response, the myocardial, to inflammatory infiltrates that happens. So we have a couple projects going on. One is to study direct effect of the immunotherapy on the cardiomyocytes and then the second angle is to take patients who are in full myocarditis and collect their patients urine samples, blood samples and to see if we could expose these IPS cardiomyocytes to the patients urine samples to see what is the effect. For these IPS cardiomyocytes for future studies we're also trying to make it more complicated by generating not just the cardiomyocytes by itself, but generating what we call engineered heart tissues. In which it's a chunk of human heart muscles that would have the patients cardiomyocytes, patients fibroblast, patients endothelial cells and expose them to the patients serum.                                                 But that kind of study would take much longer period of time because the number of people who have these types of immunotherapy induced myocarditis it's relatively low compared to patients who have Herceptin or doxorubicin induced cardio toxicity. This is also part of the reason why we're very much interested in collaborating with big centers throughout the country like York Center to see if we could understand this process better as a team. Dr Greg Hundley:             Excellent. I want to thank both of you for this really elegant discussion and perfect work moving forward. In summary, you've illustrated an ability to withdraw human pluripotent stem cells, differentiate them to cardiomyocytes and then perform tests on them to forecast susceptibility to various treatments used commonly for women with breast cancer. And in this study identifying mechanisms for trastuzumab toxicity. And then perhaps therapeutic interventions using again human cells which has a marked leap as you've identified over doing mouse studies, particularly for studying trastuzumab when the receptors the HER2 receptors in mirroring models differ substantially to those in human subjects. Dr Joseph Wu:                   Thank you Greg. And we want to also express our thanks to our collaborators, our colleagues who contributed to the study and most importantly to the patients who helped us with these studies. Dr Greg Hundley:             I want to thank both Nazish and Dr Wu from Stanford and Carolyn and I wish you the best for the coming week and we look forward to speaking with you again next week. Dr Carolyn Lam:                This program is copyright American Heart Association 2019.  

Commentary by Dr. Valentin Fuster

Episode 2 Cycling and Pollution Research Papers In this episode we discuss the findings from a research group in Canada who have recently published two papers from the same study where they had some cyclists exercise while inhaling diesel fumes. Giles, Luisa V., Christopher Carlsten, and Michael S. Koehle. 2018. “The Pulmonary and Autonomic Effects of High-Intensity and Low-Intensity Exercise in Diesel Exhaust.” Environmental Health: A Global Access Science Source 17 (1): 87. Giles, Luisa V., Scott J. Tebbutt, Christopher Carlsten, and Michael S. Koehle. 2018. “The Effect of Low and High-Intensity Cycling in Diesel Exhaust on Flow-Mediated Dilation, Circulating NOx, Endothelin-1 and Blood Pressure.” PloS One 13 (2): e0192419. Interview Interview with Dr James Tait, Institute for Transport Studies, University of Leeds who talks about his research which is more focused on characterising the dose of pollution that cyclists are subjected to in congested traffic. News Linking to the discussion in our first podcast we return to Zwift, where we talk about the idea the Zwift racing is harder than real racing. I tend to agree with this great article in Cycling Weekly https://www.cyclingweekly.com/news/11-things-know-race-zwift-407278/amp Bert de Clercq the first pro-peloton cyclist to return to top flight racing with an artificial hip. The rise of women’s pro racing, how fast are they or were the men just too slow? We discuss the incident when the women's race caught up to the men's race that had started 10 minutes earlier in the Omloop Het Nieuwsblad. Remember if you have any questions you would like us to answer then go to our website and submit your questions. www.cycling-science.com

Neben den klassischen kardiovaskulären Risikofaktoren sind psychosoziale Faktoren wie chronischer Stress oder Depression in der Genese der Atherosklerose von Bedeutung. Ob Stress dabei synergistisch zu den klassischen Risikofaktoren oder als selbstständiger Faktor die Erkrankung induziert, ist noch nicht hinreichend geklärt. Die Ergebnisse der vorliegenden Arbeit zeigen eine direkte Beeinflussbarkeit der Monozyten- und Endothelfunktion durch das Stresshormon Beta-Endorphin. Die Ergebnisse werden durch den Nachweis involvierter peripherer endothelialer und monozytärer µ1-Rezeptoren, sowie durch die erfolgreiche Blockierung der Stresshormoneffekte durch den Rezeptor-Antagonisten Naloxon bestätigt. Der Nachweis einer CRH-induzierten Stimulation der monozytären Beta-Endorphin-Synthese belegt zudem eine gegenseitige Beeinflussung beider Stresshormone. Somit ist es gelungen, einen pathophysiologischen Mechanismus einer Stress-induzierten Modifikation der Endothel- und Monozytenaktivität aufzuzeigen.

Hintergrund Die Transplantatvaskulopathie stellt eine wesentliche Ursache der Spätmorbidität und Mortalität für Patienten nach Herztransplantation dar. Durch das diffuse Befallmuster wird die Erkrankung mit Hilfe der Koronarangiographie erst in einem fortgeschrittenen Stadium erkannt. Die pathophysiologische Bedeutung der immunsuppressiven Therapie für die Entwicklung der Transplantatvaskulopathie nach Herztransplantation wird kontrovers beurteilt. Das Ziel der vorliegenden Arbeit war es, den Einfluss von zwei unterschiedlichen immunsuppressiven Regimen auf den morphologischen und funktionellen Koronarstatus zu untersuchen. Im Rahmen einer randomisierten und prospektiven Studie untersuchten wir die Veränderung des Koronarstatus bei 44 Patienten (8 weiblich, 36 männlich) im ersten Jahr nach der Herztransplantation. Verglichen wurde eine Gruppe, mit der immunsuppresiven Kombination TAC und MMF, mit einer zweiten Gruppe unter CYA und MMF. In der frühen postoperativen Phase, bis zu 6 Monaten, wurden zusätzlich Kortikoide verabreicht. Methoden In beiden Immunsuppressions-Gruppen wurde die epikardiale und mikrovaskuläre Endothel- und glatte Muskelzellfunktion, sowie die koronare Intimaverdickung 1 Monat und 1 Jahr nach der Herztransplantation bestimmt. Es sollte ermittelt werden, ob das Ausmaß der funktionellen und strukturellen Gefäßveränderungen bzw. die Progression derselben zwischen CYA und TAC-Patientengruppe unterschiedlich ist. Die endothelunabhängigen Substanzen Adenosin und Nifedipin sowie die endothel-unabhängige Substanz Acetylcholin wurden in die linke Koronararterie appliziert. Darauffolgend wurde die epikardiale Weitenänderung des Ramus interventricularis anterior an proximalen und distalen Abschnitten mittels quantitativer Koronarangiographie bestimmt. Die Änderung der koronaren Flussgeschwindigkeit (als Ausdruck der mikrovaskulären Vasoreagibilität) wurde parallel mit Hilfe eines Dopplerdrahtes in der linken Koronararterie fortlaufend gemessen. Zur frühzeitigen Erkennung der koronaren Intimaproliferation bzw. des vaskulären Remodelings erfolgte abschließend eine Untersuchung mit Hilfe des intravaskulären Ultraschalls im Ramus interventricularis anterior bzw. im Ramus circumflexus. Intimafläche, Gefäßfläche und Gefäßokklusion wurden als Parameter für strukturelle Koronargefäßveränderungen ausgewertet. Systemische Endothelin-Konzentrationen wurden mittels Radioimmunoassay nach einem und zwölf Monate nach der Transplantation bestimmt. Ergebnisse Es ergab sich ein Anstieg der mittleren Intimafläche ohne kompensatorisches vaskuläres Remodeling in der Follow-Up-Untersuchung, assoziiert mit einer signifikanten Reduktion der endothelabhängigen koronaren Flussreserve und einer (kompensatorisch) verbesserten endothelunabhängigen epikardialen Gefäßreagibilität auf Nifedipin in der CYA-Gruppe. In der TAC-Gruppe zeigte sich eine tendenzielle Zunahme der mittleren Intimafläche in der Follow-Up-Untersuchung bei gleichzeitig signifikantem Anstieg der mittleren gesamten Gefäßquerschnittfläche als Ausdruck eines positiven koronaren Remodelings. Es ergaben sich keine Unterschiede in der endothelabhängigen epikardialen Vasomotorik und in der endothelunabhängigen mikrovaskulären Vasoreagibilität im Zeitverlauf zwischen den Patienten mit TAC und CYA. Assoziiert mit den unter TAC verbesserten funktionellen und morphologischen Koronarparametern zeigte sich in der TAC-Gruppe eine signifikante Verminderung der zirkulierenden Endothelin-1 Konzentrationen im Jahresverlauf. In der CYA-Patientengruppe wurden nach einem Jahr unverändert hohe Endothelin-1-Konzentrationen gemessen. Schlussfolgerung Die Immunsuppression mit TAC und MMF scheint der mit CYA und MMF bezüglich der koronaren Gefäßokklusion und der mikrovaskulären Endothelfunktion überlegen zu sein. Pathogenetisch erscheint eine in der TAC-Gruppe verminderte Endothelin-1-Konzentration von Bedeutung zu sein. Bezüglich der epikardialen endothelabhängigen Vasomotion scheint keines der beiden immunsuppressiven Regime einen Vorteil zu haben. Weitergehende Nachbeobachtungen sind notwendig um den langfristigen Nutzen einer Immunsuppression mit TAC und Mykophenolat Mofetil für zukünftige kardiovaskuläre Ereignisse zu bestimmen.

Vorliegende Studie befasst sich mit den hämodynamischen Veränderungen sowie den Veränderungen des Endothelin-1 (ET-1) Plasmaspiegels am aortopulmonalen Shuntmodell beim Schwein. Hierzu werden in Vorversuchen die akuten hämodynamischen Veränderungen, wie sie nach Shuntimplantation auftreten, an Ferkeln im Alter von 3 bis 8 Wochen erfasst. Dabei ist ein signifikanter Abfall des mAoP sowie ein signifikanter Anstieg des mPAP, sowie PVR bei nahezu gleichbleibendem pulmonalarteriellem Fluss zu verzeichnen. Schließlich wird an 12 Absatzferkeln im Alter von durchschnittlich 32 Tagen wie auch schon bei der Vorversuchsgruppe ein aortopulmonaler Shunt mit einem Durchmesser von 6 mm und einer Länge von ca. 2 cm unter Propofolnarkose implantiert. Dabei werden vor Shuntimplantation die Basalwerte der Hämodynamik sowie des ET-1-Plasmaspiegels erfasst. Nach Shuntimplantation kommt es zu einem signifikanten Anstieg des ET-1, der sich bis zum Ende der Operation weiter erhöht. Die postoperative Mortalität der Shuntgruppe liegt bei 50%. Von diesen sterben 2 Schweine bereits wenige Stunden nach dem Eingriff an akutem Lungenödem. Der weitere Versuchsverlauf erstreckt sich über 5 Wochen. In die Kontrollgruppe gehen 4 Tiere in die Endauswertung ein, in die Shuntgruppe 6 Tiere. Bei 5 Shuntschweinen ist nach 5 Wochen der Shunt mit einem organisierten Thrombus verschlossen, lediglich bei einem Schwein ist der Shunt durchgängig. Deutliche hämodynamische Unterschiede von der Shunt- zur Kontrollgruppe bestehen zur Finalmessung im pulmonalarteriellen sowie rechtsventrikulären Druck. Die ET-1-Plasmakonzentration der Shuntgruppe ist im Vergleich zum Ausgangswert immer noch erhöht, jedoch nicht signifikant unterschiedlich zur Kontrollgruppe. In Lungenbiopsien zeigen sich nach 5 Wochen in der Shuntgruppe Parenchymverdichtungen, beim Shuntschwein mit offenem Shunt zusätzlich perivaskuläre Ödeme und Entzündungsreaktionen sowie Gefäßthromben. Zusammenfassend lässt sich sagen, dass das aortopulmonale Shuntmodell am Schwein dienliche Hinweise bezüglich der ET-1-Ausschüttung aus Endothelzellen bei erhöhtem Fluss liefert, sich jedoch wegen der Neigung zur Thrombenbildung im Shunt nicht zum Langzeitversuch eignet.

Thu, 8 May 2003 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/1043/ https://edoc.ub.uni-muenchen.de/1043/1/Unterlinner_Silke.pdf Unterlinner, Silke ddc:610, ddc:600, Medizinische F

Im Rahmen dieser Arbeit wurde zum ersten Mal die PKC-vermittelte Inhibition der EGF-induzierten JNK-Aktivität durch GPCRn gezeigt, die durch Transmodulation des EGF Rezeptors verursacht wird. Darüber hinaus wurde anhand einer dominant negativen Mutante der Effekt von PKD auf diesen Prozess nachgewiesen und ihre Rolle in der bereits durch (Bagowski et al., 1999) beschriebenen PDGF-vermittelten JNK-Inhibition verifiziert. Weiterhin wurde gezeigt, dass die Liganden Endothelin und LPA, die ihre Signale über ver-schiedene G-Proteine vermitteln, in Rat1-Zellen über die Aktivierung von PKD unterschiedliche Signalwege verfolgen. So vermittelt Endothelin, welches PKD über Gq-Proteine aktiviert, ebenso wie PDGF die Inhibition der EGF-induzierten JNK-Aktivierung. Hingegen führt LPA, welches PKD zusätzlich über Gi-Proteine stimuliert, zu einer Verdopplung der EGF-induzierten JNK-Aktivität. Neben der EGF Rezeptortransmodulation wurden in dieser Arbeit Untersuchungen zu seiner Transaktivierung durchgeführt. Hier wurde zum ersten Mal die PKC-abhängige Transaktivierung des EGF Rezeptors durch PDGF gezeigt. Hierbei werden dazu in Rat1-Zellen Phor-bol-ester-abhängige PKCs, in 3T3 L1-Zellen dagegen Phor-bol-ester-unabhängige PCKs benötigt. Weiterhin wurde im Rahmen dieser Arbeit die konstitutive Assoziation von PKD mit dem PDGF Rezeptor nachgewiesen, die sowohl in gesunden Nagetierzellen als auch in humanen Glioblastomzellen stattfindet. Verantwortlich für diese Bindung scheint der Juxtamembranbe-reich des PDGF Rezeptors zu sein, während bei PKD mit hoher Wahrscheinlichkeit der Carbo-xyterminus involviert ist. Auch die aus B-Zellen bereits bekannten Interaktionen von PKD mit PLC und Syk (Sidorenko et al., 1996) wurden untersucht, und die PDGF-induzierte Assoziation von PKD mit PLC in denselben Systemen nachgewiesen, in denen auch die Assoziation von PKD mit dem PDGF Rezeptor gezeigt wurde. Eine Assoziation von PKD mit Syk fand sich dagegen nur in HEK 293-Zellen, die PKD und Syk überexprimierten.

Die neuroendokrine Aktivierung spielt bei der Entwicklung und Progression der chronischen Herzinsuffizienz sowohl im Rahmen der Pathophysiologie als auch als Ansatzpunkt einer möglichen medikamentösen Intervention eine bedeutende Rolle. In der Therapie der chronischen Herzinsuffizienz konnte durch den Einsatz von ACE-Hemmern nicht nur eine Verbesserung der Symptomatik, sondern auch eine Verringerung der Mortalität erreicht werden. Ziel der hier vorgelegten klinischen Studie war es, den Einfluss des ACE-Hemmers Perindopril auf die neurohumoralen Parameter Renin, Aldosteron, Atrialer Natriuretischer Faktor (ANF), zyklisches Guanosinmonophosphat (cGMP), Endothelin-1, sowie Vasopressin bei Patienten mit chronischer Herzinsuffizienz zu untersuchen. Die gewonnen Daten wurden zudem mit den im Rahmen einer parallel laufenden Untersuchung erfassten hämodynamischen Messwerten korreliert, um nähere Aufschlüsse über den Zusammenhang zwischen hämodynamischen Verhältnissen und dem dabei vorliegenden Grad der neurohumoralen Aktivierung zu erhalten. Weiterhin sollten durch die Ermittlung der Korrelationen zwischen den einzelnen neurohumoralen Parametern weitere Aufschlüsse über die bestehenden Zusammenhänge zwischen den neurohumoralen Systemen erhalten werden. Die Erhebung der Daten erfolgte im Rahmen einer doppelblinden placebokontrollierten Studie über 24 Wochen, an 25 Patienten mit chronischer Herzinsuffizienz im Stadium NYHA II-III aufgrund von dilatativer Kardiomyopathie oder koronarer Herzerkrankung. Die tägliche Dosierung von Perindopril betrug dabei zu Studienbeginn 2 mg und wurde bei Verträglichkeit auf 4 mg erhöht. Es wurden die Plasmaspiegel der untersuchten Neurohormone wie auch die hämodynamischen Parameter Belastungstoleranz, Herzfrequenz, sowie systolischer und diastolischer Blutdruck bei Untersuchungsbeginn, sowie nach 4, 12 und 24 Wochen erfasst. Die Bestimmung der linksventrikulären Auswurffraktion erfolgte zu Studienbeginn sowie nach 12 und 24 Wochen, die des kardiothorakalen Quotienten zu Beginn und am Ende der Studie. Perindopril führte zu einem Anstieg des mittleren Renin-Plasmaspiegels, der zu allen Untersuchungszeitpunkten das Signifikanzniveau sowohl im Vergleich zum Untersuchungsbeginn als auch im Vergleich zur Placebogruppe erreichte. Der Plasmaspiegel von Aldosteron lag zu allen Untersuchungszeitpunkten in der Verumgruppe unterhalb des Ausgangsniveaus, ein signifikanter Unterschied im Vergleich mit dem Untersuchungsbeginn konnte jedoch nicht erreicht werden. Nur zum Zeitpunkt 12 Wochen bestand ein signifikanter Unterschied im Vergleich zur Placebogruppe. Diese Ergebnisse weisen auf eine langanhaltende Hemmung des Angiotensin-Converting-Enzyms während des gesamten Untersuchungsverlaufes durch Perindopril hin. Ob eine Dosiserhöhung zu einer stärkeren Suppression des Aldosteronspiegels führt, sollte durch weitere Untersuchungen geklärt werden. Perindopril führte zu keiner signifikanten Änderung des ANF-Plasmaspiegels während des gesamten Untersuchungsverlaufes. Der Plasmaspiegel von cGMP wurde durch Perindopril gesenkt, ein Signifikanzniveau konnte aber nur zum Zeitpunkt 4 Wochen im Vergleich zum Studienbeginn erreicht werden. Auch hier sollte geprüft werden, ob eine Dosiserhöhung von Perindopril zu einem stärkeren Einfluss auf diese Parameter führen kann. Überraschenderweise kam es in der Verumgruppe zu einem Anstieg des Plasmaspiegels von Endothelin-1, der das Signifikanzniveau zu den Zeitpunkten 12 und 24 Wochen im Vergleich zum Studienbeginn erreichte. Durch weitere Untersuchungen sollte geklärt werden, ob es sich hier um eine substanzspezifische Wirkung von Perindopril handelt. Eine Beeinflussung des Vasopressin-Plasmaspiegels durch Perindopril konnte nicht gezeigt werden. Eine signifikante lineare Korrelation innerhalb der neurohumoralen Parameter ergab sich nur für ANF und cGMP sowie in schwächerer Form für cGMP und Vasopressin. Zwischen hämodynamischen und neurohumoralen Messgrößen ergaben sich für ANF und cGMP signifikante positive lineare Korrelationen mit der linksventrikulären Auswurffraktion sowie negative Korrelationen mit dem kardiothorakalen Quotienten. Für Vasopressin konnte eine schwache positive lineare Korrelation mit dem diastolischen Blutdruck und der Herzfrequenz nachgewiesen werden. Auffallend war eine starke Streuung der Einzelwerte sämtlicher gemessener Plasmaspiegel. Die Ergebnisse zeigen, dass die Aktivierung der einzelnen neurohumoralen Systeme nicht parallel, sondern interindividuell verschieden und komplex verläuft. Nur für cGMP als second messenger konnte eine Koinzidenz mit ANF nachgewiesen werden. Ansonsten ist der Rückschluss von der Aktivierung eines neurohumoralen Systems auf ein anderes bei Patienten mit Herzinsuffizienz im Stadium NYHA II-III nicht möglich. Von den gemessenen neurohumoralen Parametern haben nur die Plasmaspiegel von ANF und vor allem cGMP eine verwertbare Aussagekraft als humorale Marker für die linksventrikuläre Funktion bei Patienten mit chronischer Herzinsuffizienz im Stadium NYHA II-III.

Thu, 1 Jan 1998 12:00:00 +0100 https://epub.ub.uni-muenchen.de/16876/1/10_1159_000051412.pdf Bilzer, Manfred; Gülberg, Veit; Gerbes, Alexander L. ddc:610,

Sat, 1 Jan 1994 12:00:00 +0100 https://epub.ub.uni-muenchen.de/8206/1/determination_of_endothelin-1_immunoreactivity_in_plasma_cerebrospinal_fluid_and_urine_8206.pdf Goebel, Frank-Detlef; Bogner, Johannes R.; Sadri, Ifna; Rolinski, B.

Sat, 1 Jan 1994 12:00:00 +0100 https://epub.ub.uni-muenchen.de/8200/1/8200.pdf Goebel, Frank-Detlef; Ehrenreich, H.; Bogner, Johannes R.; Klauss, Volker; Sadri, Ifna; Geier, Stephan A.; Rolinski, B.

Inhaltsverzeichnis fehlt.

A highly specific and sensitive radioimmunoassay (RIA) has been established for determination of endothelin-3 like immunoreactivity in human plasma to investigate its possible role in hemodynamic alterations due to liver disease. Crossreactivity with other endothelin isoforms was always below 4 %, the lower detection limit following extraction on Sep-Pak C18 cartridges was 0.5 pg/ml. The concentration of endothelin-3 (mean ± SEM) was 4.16 ± 0.56 pg/ml (n = 13) in plasma of patients with cirrhosis of the liver, three fold higher than in age matched controls (1.35 ± 0.27 pg/ml, n = 12, p < 0.01). Plasma immunoreactivity was confirmed to be endothelin-3 related by reverse-phase HPLC. These data could suggest a role of plasma endothelin-3 in circulatory changes, as they occur in cirrhosis of the liver.