Podcasts about peking union medical college

Beijing municipal health authority has revoked the medical licenses of a former senior surgeon and a resident physician at a major Beijing hospital for violations of professional ethics and academic misconduct, the National Health Commission said on Thursday.国家卫生健康委员会周四表示，北京市卫生局已吊销北京一家大型医院原资深外科医生和住院医师的行医执照，原因是他们违反职业道德和学术不端行为。The disciplinary action follows an official investigation that attracted widespread public attention after the two doctors' extramarital affair and personal misconduct emerged in April. The case has prompted scrutiny of loopholes in surgical oversight, professional ethics and medical school admissions.自今年4月这两名医生的婚外情和个人不当行为曝光以来，官方对此展开了调查，并引发了广泛关注。此次纪律处分是在此之前做出的。此案引发了人们对外科监管、职业道德和医学院招生方面漏洞的反思。According to the commission, the former senior surgeon, surnamed Xiao, arbitrarily left an operating room mid-surgery while the patient was under anesthesia. He departed along with his assistant following an argument with a nurse at China-Japan Friendship Hospital in July.据该委员会称，这位姓肖的原资深外科医生在手术过程中，在患者麻醉期间擅自离开手术室。7月份，他与助手在中日友好医院与一名护士发生争执后离开。"He prioritized personal emotions over patient safety and failed to understand his responsibilities as a physician, and the potential medical risks posed to the patient by his actions," the commission said in a statement.该委员会在一份声明中表示：“肖医生将个人情感置于患者安全之上，未能理解其作为医生的责任，也未能理解其行为可能给患者带来的医疗风险。”Xiao's extramarital relationship with the resident physician, surnamed Dong, also constituted "a severe violation of professional and medical ethics" and caused "significant negative social impact", it said.肖某与住院医师董某的婚外情也构成了“严重违反职业道德和医德行为”，并造成了“重大不良社会影响”。Xiao was dismissed from the hospital and expelled from the Communist Party of China earlier this month. His medical license has been revoked by the Beijing municipal health authority, and he is banned from practicing medicine for at least five years. The hospital received a formal warning, a corrective order and financial penalties.本月初，肖某被医院开除出党，并被开除党籍。他的行医执照已被北京市卫生部门吊销，并被禁止至少五年内行医。医院收到了正式警告、责令改正和经济处罚。Dong, who graduated from an elite medical training program in China, was involved in a sexual relationship with Xiao during her residency, according to a letter published by Xiao's wife in April.据肖某妻子今年4月发表的一封信称，董某毕业于中国一所精英医学培训项目，在院期间与肖某发生了性关系。Authorities said Dong falsified academic records to gain admission to a four-year doctoral program at Peking Union Medical College—one of China's most prestigious medical schools. Her dissertation was found to contain serious instances of plagiarism, and several of her academic papers involved violations of research integrity, including improper authorship and duplicate publications.当局表示，董某伪造学术记录，以便进入中国最负盛名的医学院之一——北京协和医学院攻读四年制博士学位。她的学位论文被发现存在严重抄袭行为，她的多篇学术论文涉及违反科研诚信的行为，包括署名不当和重复发表。Peking Union Medical College has revoked Dong's degree and graduation credentials. Local health authorities have also revoked her medical qualification and license, according to the commission.北京协和医学院已撤销董某的学位和毕业证书。据该委员会称，当地卫生部门也已吊销了她的医师资格和行医执照。The "four-plus-four-year" doctoral program that admitted Dong combines undergraduate and medical studies and targets top international university graduates from nonmedical fields. It was designed to integrate medical education with interdisciplinary training and to reform the traditional eight-year path to becoming a doctor in China.董某的“四年加四年”博士研究生项目融合了本科和医学教育，面向非医学领域的国际顶尖大学毕业生。该项目旨在将医学教育与跨学科培训相结合，改革中国传统的八年制医生培养模式。The commission said the case has exposed flaws in the program's admission criteria, clinical training supervision, thesis review procedures and student ethics education.该委员会表示，此案暴露了该项目在招生标准、临床实习督导、论文评审程序和学生伦理教育方面存在的缺陷。"Peking Union Medical College is currently undergoing thorough rectification," the commission said. "The commission is working with the Ministry of Education to conduct a comprehensive evaluation of the pilot program and promote reforms."该委员会表示：“北京协和医学院目前正在进行彻底整改。委员会正会同教育部对试点项目进行全面评估，并推进改革。”The commission is carrying on deeper probe into institutions and personnel involved in the case and will hold those violating rules and regulations accountable.该委员会正在对涉案机构和人员进行深入调查，并将追究违规人员的责任。revocation/ˌrevəˈkeɪʃn/n.撤销，吊销misconduct/ˌmɪsˈkʌndʌkt/n.不当行为；失职plagiarism/ˈpleɪdʒərɪzəm/n.抄袭；剽窃rectification/ˌrektɪfɪˈkeɪʃn/n.整改；纠正

When Tian Xiaorun, a male teacher in Hangzhou, Zhejiang province, flew to the Hong Kong special administrative region to be vaccinated against HPV in January, his friends and family members questioned his decision.浙江省杭州市的男教师田晓润今年1月飞往香港特别行政区接种人乳头瘤病毒疫苗，他的朋友和家人对他的决定表示疑惑。"Even the doctor in Hong Kong was surprised to see me — a male from the mainland — come to get vaccinated against HPV," said the 30-year-old.30岁的他说：“看到我一个来自内地的男性来接种人乳头瘤病毒疫苗，连香港的医生都感到惊讶。”HPV vaccines are mainly used to prevent cervical cancer, which kills 342,000 women a year worldwide. But men also benefit from getting vaccinated to protect against genital and colon cancers and those in the head and neck, among others. Some countries and regions have approved HPV vaccines for use among both genders.HPV疫苗主要用于预防宫颈癌，全世界每年有34.2万名妇女死于宫颈癌。但男性也可以通过接种疫苗来预防生殖器癌、结肠癌以及头颈部癌症等。一些国家和地区已经批准男性和女性接种人乳头瘤病毒疫苗。"I first learned that men could receive vaccines against HPV when I was an exchange student in the United States, but at that time, I simply shrugged off the risk of the virus," he said.他说：“我在美国做交换生时第一次知道男性可以接种人乳头瘤病毒疫苗，但当时我只是简单地回避了病毒的风险。”"The COVID-19 pandemic prompted me to increase self-care, and after doing some research, I believe that getting vaccinated is worthwhile because it would not only protect myself against genital warts, but also my female partners."“新冠疫情促使我加强自我保健，在做了一些研究后，我认为接种疫苗是值得的，因为这不仅能保护自己免受生殖器疣的侵害，还能保护我的女性伴侣。”A small but growing number of men in China have considered or opted to obtain HPV vaccines outside the mainland — where the dose is not currently approved for use among men.中国有一小部分男性考虑或选择在中国大陆以外的地区接种人乳头瘤病毒疫苗，但这一人数在不断增加。While hailing the growing awareness and acceptance of the cancer-preventing shot, experts said that in China, the priority group for HPV vaccination remains females aged 9 to 45, especially young girls and adolescents.专家们对越来越多的人认识和接受这种预防癌症的疫苗表示欢迎，但同时表示，在中国，接种HPV疫苗的重点人群仍然是9至45岁的女性，尤其是少女和青少年。Wu Yinglan, director of the women's health department at the Hunan Provincial Maternal and Child Health Hospital, said that men could not only prevent HPV-related conditions by getting the vaccine, but could also protect their female partners by lowering women's risk of exposure to HPV viruses via sexual contact.湖南省妇幼保健院妇女保健科主任吴颖岚说，男性不仅可以通过接种疫苗预防与HPV相关的疾病，还可以通过降低女性通过性接触接触HPV病毒的风险来保护他们的女性伴侣。"Cervical cancer is common and deadly for females. As the domestic manufacturing capacity of HPV vaccines is not large enough to protect both men and women, we should prioritize female vaccination," she said during an interview with Xiaoxiang Morning Herald, a newspaper based in Hunan province.“宫颈癌是女性常见的致命疾病。”她在接受《潇湘晨报》采访时说：“由于国内HPV疫苗的生产能力不足以同时保护男性和女性，我们应该优先考虑女性接种。”"In case of sufficient supplies in the future, mass vaccination for both men and women could become a trend," she added.她补充说：“在未来供应充足的情况下，为男性和女性大规模接种疫苗可能会成为一种趋势。”Qiao Youlin, a professor at the School of Population Medicine and Public Health at Peking Union Medical College, said during a previous interview that HPV vaccines should be prioritized for girls aged under 15.中国医学科学院北京协和医学院特聘教授乔友林此前在接受采访时说，应优先为15岁以下的女孩接种人乳头瘤病毒疫苗。"Human papillomavirus is mainly transmitted through sexual contact, and males should get vaccinated but they are only the third priority," he said.他说：“人类乳头瘤病毒主要通过性接触传播，男性应该接种疫苗，但他们只是第三优先。”Cho Kyu-hyun, a South Korean singer and television host, said during a recent television program that he had obtained his first HPV vaccine. He said he hoped his decision could help break stereotypes about the vaccine as a female-exclusive product and spread awareness about the significance of preventing HPV infections.韩国歌手兼电视节目主持人曹圭贤在最近的一次电视节目中说，他已经接种了第一针人乳头瘤病毒疫苗。他说，他希望自己的决定有助于打破疫苗是女性专属产品的陈旧观念，并提高人们对预防人乳头瘤病毒感染重要性的认识。A hashtag related to his vaccination became one of the most-discussed topics on China's microblogging platform Sina Weibo on Aug 9.8月9日，一个与曹圭贤接种疫苗有关的标签成为中国微博平台新浪微博上讨论最多的话题之一。Some netizens said they were surprised to learn that men could get HPV vaccines and applauded his move, while some said even their female friends have not been vaccinated yet due to low awareness and limited supplies.一些网民表示，他们对男性可以接种HPV疫苗感到惊讶，并为曹圭贤的举动点赞；而一些网民则表示，由于认识不足和供应有限，甚至他们的女性朋友也还没有接种疫苗。Chai Yan, director of consulting firm IQVIA Biotech, said that HPV vaccination coverage among women aged 4 to 45 is uneven across China. More efforts are needed to boost inoculation rates in small cities and towns, as well as for younger girls aged 9 to 15.咨询公司IQVIA Biotech的主任柴岩说，中国4至45岁女性的HPV疫苗接种覆盖率参差不齐。需要加大力度提高小城市和乡镇的接种率，以及9至15岁年轻女孩的接种率。He added that several domestic vaccines are projected to gain market approval by around 2026, which will greatly boost the country's manufacturing capacity.他补充说，预计到2026年左右，将有几种国产疫苗获得市场批准，这将大大提高中国的生产能力。Cervical 英/ˈsɜːvɪk(ə)l/ 美/ˈsɜːrvɪk(ə)l/adj.颈的；子宫颈的Vaccinate英/ˈvæksɪneɪt/ 美/ˈvæksɪneɪt/v.给……接种疫苗；接种疫苗

In this episode I am returning to explore the truth about the Chernobyl disaster. I have the great fortune to interview one of the doctors who treated the exposed workers in Moscow following the explosion.  Let's see what he thinks of the health risks of nuclear power. Robert Peter Gale was born in New York in 1945. He received his MD from the State University of New York at Buffalo and PhD in microbiology and immunology from the University of California, Los Angeles (UCLA). After that Gale was on the faculty of the UCLA School of Medicine, and served as Chairman of the Scientific Advisory Committee of the Center for International Blood and Marrow Transplant Research, and later chaired the Scientific Advisory Board of the Center for Advanced Studies in Leukemia. He was President of the Armand Hammer Center for Advanced Studies in Nuclear Energy and Health. Gale is currently Visiting Professor of Haematology at Sun Yat-sen Cancer Centre, Guangzhou, China and Honorary Professor of Hematology at the Institute of Hematology at Peking Union Medical College. He is the Editor-in-Chief of LEUKEMIA, Associate Editor of CLINICAL TRANSPLANTATION, Executive Editor of BONE MARROW TRANSPLANTATION and a reviewer for many scientific journals in hematology, oncology, immunology, transplantation, radiation biology and internal medicine. Prof. Gale is also an expert on the medical response to nuclear and radiation accidents. From 2007-2019 he was executive director of clinical research and development at Celgene Corp and an honorary member of the Russian and Chinese Academies of Medical Science. He is the recipient of several distinguished awards and honorary degrees including the Presidential Award, and an Emmy award. Gale has published over 1,350 scientific articles and 25 books on medical topics, nuclear energy and weapons and politics of US-Russian relations and received an Emmy award. His latest book is “Radiation: What it is, What you need to Know”. Support the podcast at patron.podbean.com/TheRationalView Join the Facebook discussion @TheRationalView Twitter @AlScottRational Watch the video version on YouTube! #TheRationalView #podcast #chernobyl #nuclearenergy #radiation #health

This week, please join authors Kevin Roedl and Sebastian Wolfrum, as well as Associate Editor Mark Link as they discuss the article "Temperature Control After In-Hospital Cardiac Arrest: A Randomized Clinical Trial." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary, and backstage pass to the Journal and its editors. We are your cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, very interesting, a randomized clinical trial of temperature control after in-hospital cardiac arrest. But before we get to that exciting study, let's grab a cup of coffee, and jump in and discuss some of the other articles in the issue. Carolyn, would you like to go first? Dr. Carolyn Lam: Yes. Starting with a great quiz. So Greg, which is better? How about this? It's multiple choice. Is it A; transradial, or B; transfemoral access, in terms of post-procedural mortality? Dr. Greg Hundley: I'm going to go with transradial. It has been, hopefully, I'm okay on this. It just seems so many fewer complications. Dr. Carolyn Lam: But that's exactly that we need to meta-analyze the studies that have been done. Exactly what this paper did, led by Professor Valgimigli, from USI in Lugano, Switzerland. So what they did is, they performed an individual patient data meta-analysis of 21,600 patients, enrolled in seven multi-center randomized control trials, comparing the transradial with transfemoral access, among patients undergoing coronary angiography with or without PCI. And they found that transradial access was associated with a lower incidence of the primary outcome of all-cause mortality, and the co-primary outcome of major bleeding at 30 days, compared to transfemoral access. There was also evidence for reductions in major adverse cardiac and cerebral vascular events, net adverse clinical events, vascular complications, excess site bleeding, and blood transfusion. MI, stroke, and stent thrombosis, did not differ. And crossover was higher in the transradial access group. At predefined subgroup analysis, the authors confirmed that the benefit observed the transradial group was generally consistent across the majority of pre-specified subgroups, except for those with significant baseline anemia. Patients with baseline anemia appear to derive a substantial mortality benefit with transradial access rather than transoral access, compared to those with mild or no anemia. So, the authors concluded, that the meta-analysis provides evidence that transradial access should be considered the preferable access site for PCI, in patients with acute coronary syndrome, supporting most recent recommendations on the preferential use of this radial approach. So you were right, Greg. Dr. Greg Hundley: Very nice, Carolyn. A really important piece of science to disclose to our listeners, in that hurried state, and moving quickly door to balloon times, et cetera. And here we find another positive outcome in study result for transradial approaches. Well Carolyn, as we know, my next paper, it's really going to come to us from the world of preclinical science. And it pertains to hypertension, which is a common cardiovascular disease, and is related to both genetic and environmental factors. But the mechanisms linking the interplay between the domains of genetics and the environment have not been well studied. Now, DNA methylation, a classical epigenetic modification, not only regulates gene expression, but is also quite susceptible to environmental factors. Thereby, linking environmental factors to genetic modifications. So therefore, Carolyn, these authors, including Professor Jingzhou Chen, from Fuwai Hospital, National Center for Cardiovascular Diseases, and the Chinese Academy of Medical Sciences, and the Peking Union Medical College, and their colleagues, felt that screening differential genomic DNA methylation, in subjects with hypertension, would be important for investigating this genetic environment interplay in hypertension. So this study, Carolyn, like many from the world of preclinical science and circulation, incorporated both human and animal model subjects. Methodologically differential genomic DNA methylation in hypertensive, pre-hypertensive, and healthy control individuals, was screened using the Illumina 450K BeadChip, and then verified by pyrosequencing. Plasma oviduct glycoprotein 1, or OVGP1 levels, were determined using an enzyme-linked immunosorbent assay. And OVGP1 transgenic and knockout mice were generated to analyze the function of OVGP1. Dr. Carolyn Lam: Wow. Nice approach, Greg. And what did the authors find? Dr. Greg Hundley: Right, Carolyn. These authors found a hypomethylated site at cg20823859 in the promoter region of OVGP1, and the plasma OVGP1 levels were significantly increased in hypertensive patients. This finding indicates that OVGP1 is associated with hypertension. Now Carolyn, in OVGP1 transgenic mice, OVGP1 over expression caused an increase in blood pressure. Also, dysfunctional vasoconstriction, and vasodilation, remodeling of the arterial walls, and increased vascular superoxide stress and inflammation. And these phenomenon were exacerbated by angiotensin II infusion. In contrast, OVGP1 deficiency, attenuated angiotensin II induced vascular oxidase, stress, inflammation, and collagen deposition. Now pull down, and co-immunoprecipitation assays showed that myosin heavy chain 2A, or MYH9, interacted with OVGP1. Whereas, inhibition of MYH9 attenuated OVGP1 induced hypertension and vascular remodeling. Dr. Carolyn Lam: So Greg, let me try to summarize, is that okay? So hypomethylation, at that specific site in the promoter region of the OVGP1 gene, is associated with hypertension, and induces its upregulation. The interaction of this OVGP1 with myosin heavy chain 2A contributes to vascular remodeling and dysfunction. And so, OVGP1 is a pro hypertensive factor, that promotes vascular remodeling by binding to this myosin heavy chain. So, really cool stuff. Thanks for teaching us. Dr. Greg Hundley: Very good. Dr. Carolyn Lam: Well thanks so much, Greg. And we go back to the clinical world now, and ask the question, what is the efficacy and safety of prophylactic full dose anticoagulation and antiplatelet therapy, in critically ill COVID-19 patients? So I'm going to tell you the results of the COVID-PACT trial. And this was a multi-center, two-by-two factorial, open label, randomized controlled trial, with blinded endpoint adjudication in 390 ICU level patients. So, severely ill patients with COVID-19, from 34 US centers. Patients were randomized to a strategy of full dose anticoagulation, or standard dose prophylactic anticoagulation. And in the absence of an indication for antiplatelet therapy, patients were additionally randomized to either clopidogrel or no antiplatelet therapy. Dr. Greg Hundley: Ah, Carolyn. So what did they find? Dr. Carolyn Lam: Full dose anticoagulation substantially reduced the proportion of patients experiencing a venous or arterial thrombotic event, and there was no benefit from treatment with clopidogrel. Severe bleeding events were rare, but numerically increased in patients on full dose versus standard dose prophylactic anticoagulation, without any fatal bleeding events, GUSTO moderate or severe bleeding was so significantly increased with full dose anticoagulation, but with no difference in all-cause mortality. So in summary, in a population of critically ill patients with COVID-19, a strategy of prophylaxis with full dose, versus standard dose prophylactic anticoagulation, but not the addition of clopidogrel, reduced thrombotic complications, with an increased risk of bleeding, driven primarily by transfusions in hemodynamically stable patients, with no apparent excess in mortality. Dr. Greg Hundley: Very nice, Carolyn. What a important piece of information, as many of us around the world are taking care of critically ill patients with COVID-19. Well, how about we see what is in the mail bag this week? So first, Carolyn, there's a Frontiers piece by Dr. Packer, entitled, “Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 inhibitors, and Reaffirmation of the Nutrient Deprivation Signaling Autophagy Hypothesis.” Next, there's a Research Letter, from Professor Airaksinen entitled, “Novel Troponin Fragmentation Assay to Discriminate Between Troponin Elevations in Acute Myocardial Infarction and End-stage Renal Disease.” Carolyn, there's another Research Letter, from Professor Solomon, entitled, “Aptamer Proteomics for Biomarker Discovery in Heart Failure with Reduced Ejection Fraction.” Also, Carolyn, [a] wonderful Cardiovascular News summary from Tracy Hampton, reviewing three articles. First, “Mechanisms Behind Cannabis Effects on Heart Health.” The second, “Exercise Inducible Metabolite Suppresses Hunger.” And then lastly, “Piezo1 Initiates the Cardiomyocyte Hypertrophic Response to Pressure Overload.” Dr. Carolyn Lam: Cool. There's also an exchange of letters between Doctors Jha and Borlaug on latent pulmonary vascular disease in therapeutic atrial shunt. And finally, an On My Mind, by Dr. David Kass entitled, “What's EF Got To Do, Got To Do With It.” I love it. You must read it. It's so, so cool. All right. But now, let's go on to our feature discussion, shall we? Dr. Greg Hundley: You bet, Carolyn.   Welcome listeners, to our feature discussion today, and really delving into the world of in-hospital cardiac arrest, and how we manage those patients. And we have with us today, Dr. Kevin Roedl from Hamburg, Germany, Dr. Sebastian Wolfrum from Lubeck, Germany, and our own associate editor, Dr. Mark Link from University of Texas Southwestern in Dallas, Texas. Welcome gentlemen. Kevin, we're going to start with you. Can you describe for us, some of the background information that went into the construct of your study, and what was the hypothesis that you wanted to address? Dr. Kevin Roedl: Thank you, Greg. We thank you for the kind invitation to this podcast. We're very likened to do this podcast with you. And so, talking about the background of hypothermia in-hospital cardiac arrest, we have to go back like two decades almost, because there were two studies in New England Journal of Medicine published 2002, who introduced mild therapeutic hyperthermia to the treatment in post cardiac arrest. Primary, these two studies show the benefit of the therapy in this kind of patients. And then, 2003, it was introduced in also the international guidelines. However, these studies only addressed out-of-hospital cardiac arrest patients, and also, only shockable rhythms. And so, the question arised over the years, what about other patients like non shockable rhythms, or also in-hospital cardiac arrest? And so, that's basically was the primary aim of our study to address this special population. Because when you see the states, the numbers, there are 290,000 in-hospital cardiac arrests a year. So it's actually, a very large population. And there's no randomized control trial to show any benefit, or maybe harm, in this group. There were some observational studies, 2016 in China published. From China, in this group, they looked at the Get With The Guidelines registry, and actually, they saw that there was probably a negative influence of hypothermia in the study. However, it was only observational. So actually, there were no randomized control trials. And that primary hypothesis was, that we wanted to know actually, does thus mild therapeutic hyperthermia work in this group of patients in the in-hospital cardiac arrest setting? And what is the outcome? Is it like in the out-of-hospital cardiac arrest setting, or not? Dr. Greg Hundley: Wonderful, Kevin. And so, can you describe for us then, your study population and your study design? Dr. Kevin Roedl: Yes, of course. We did a randomized control trial. There were over 1000 people screened, and overall, we included 242. So you see how hard it is to get people in there. And actually, in terms of hypothermic temperature control, we are 120 about, and long term at 118, and the final others of the endpoints. And when we look at the baseline characters of these patients, they were well balanced actually, about 72 years. When we look at the initial cardiac arrest rhythm, that's interesting because about 70% non-shockable rhythms, and 25% shockable rhythms. And probably also interesting, the location of the cardiac arrest. Medical boards about 50%, and ICU or ED was 22%. So that's probably summed up the baseline characteristics of our study. Dr. Greg Hundley: Perfect. And so Kevin, can you describe for us what was the hypothermic target for the group that was going to have their temperature recused? Dr. Kevin Roedl: Yes, hypodermic target was 32 degrees to 44. And so two degrees Celsius, basically the same target like in earlier trials. Dr. Greg Hundley: Very nice. Well listeners, now we're going to turn to our second co-author, Dr. Sebastian Wolfrum. And Sebastian, can you share with us the study results? Dr. Sebastian Wolfrum: Yes, Greg. Thank you very much for the opportunity to participate in this podcast. Only wanted to include unconscious patients, and therefore, we took a time and took 45 minutes after their cardiac arrest, to let the patients get away if they did so. We also excluded patients that had severe functional deficit before the cardiac arrest; since we could not really define the neurological outcome if we would've included those. And we didn't see any differences. Neither in mortality, not in the functional outcome, either when they're treated with 33 degrees Celsius, or whether normothermia was used. The death rate after six month was in a range which is comparable to other in-hospital cardiac arrest studies, and higher than those performed in the out-of-hospital cardiac arrest studies. It was about slightly over 70% in both groups. And the number of patients with the good functional recovery after six months was 23% of the patients in the hypothermia group, and 24% of the patients in the normothermia group. And if we look at only the survivors, we see that the ones which are worse functional outcome, were most of them dead after six months. We then also focused on the temperature curves in our patients, and to see whether we have achieved our goal. And we saw that we have reached the target temperature within four and a half hours after cardiac arrest in our hypothermia group. Which is not as fast that we had expected, but still in the range, which is comparable to other studies on this field. And we also saw that our control group was about 37 degrees, within the first 12 and 48 hours. So we truly avoided fever, which has not been done in every previous study on cardiac arrests. Dr. Greg Hundley: Very nice. And any differences between the hypothermia and normothermia groups, related to the age of the patient? Or, whether or not they had a shockable rhythm at the time of presentation? Dr. Sebastian Wolfrum: We saw as a result of our study, that age is a predictive factor for mortality. But age did not differ between our treatment groups, and therefore, did not interfere with our results. And we didn't see differences in the shockable or non-shockable rate in our patients in the different treatment groups.   Dr. Greg Hundley: Thank you. Well listeners, now we're going to turn to our associate editor, Dr. Mark Link, one of our expert electrophysiologists at Circulation. And Mark, you have many papers come across your desk, and what attracted you to this particular paper? Dr. Mark Link: There were a number of things. One, it's hard to do RCTs in resuscitation, and I thought they did a very nice job with this RCT. Two, the subject of hypothermia, or therapeutic temperature management, is a very hot one in resuscitation. It's one of the few treatments in the past that have been shown to make a difference in outcome. And so, all of those trials were done in out-of-hospital arrest. So to have a trial done in in-hospital arrest was very intriguing also. And I think we're all disappointed that it wasn't a positive trial, but we have to take the negative trials also. And I think, part of the reason it may have been a negative trial is because the normal thermic group avoided hyperthermia. And I think that's something that's coming out of a lot of these trials is avoid fever. It may not be so important to get hypothermic targets, actually, looks like it's probably not, but it looks like it's very important to avoid fever. Dr. Greg Hundley: Very nice. Well listeners, we're going to turn back to our expert panel here really, and start with you Kevin. Kevin, what do you think is the next study that needs to be performed in this sphere of research? Dr. Kevin Roedl: Thank you for this interesting question. Yeah, a bunch of studies could be performed, especially maybe in the out-of-hospital cardiac arrest study, because we don't know. This fever harmful, we have to find certain subgroups in which this treatment works. So maybe in this subgroups there is data on this and it could be a benefit. So these are, I think, the two main topics that should be done in the future. Dr. Greg Hundley: Thank you. Sebastian, what are your thoughts? Dr. Sebastian Wolfrum: As Mark said, the hypothermic treatment was, for decades, maybe the only treatment which we could give to cardiac arrest patients, which has been proven to reduce mortality. And all other studies following didn't see any be benefit of hypothermia, not even in a subgroup. Also, the TTM trials did not. So I'm questioning myself, where is the original HACA study group that benefits? Where did this hide in the other studies? So I would think, to do another study in out-of-hospital cardiac arrest patients, whether in ventricular fibrillation that had shown in the HACA trial to reduce mortality. This should be done in a similar way to the original study, to see whether there is this subgroup. People who support the idea of hypothermia also focus very much on the fast onset of their hypothermic treatment. And they say we saw a difference in mortality in the HACA trial, and we could very fast. And I think the other studies have to show that they cool as fast as the HACA study. So the main focus should be on the time calls of hypothermia after cardiac arrest, cooling very fast to a target temperature of 33 degrees, maybe holding on for 24, maybe 48 hours. Dr. Greg Hundley: Very nice, Sebastian. So focusing on the speed and the timing of that cooling. And Mark, anything to add? Dr. Mark Link: Yeah, so if I sit here with my writing group hat on for the HA and say, "What are we going to do for the resuscitation guidelines in 2025?" I think you look at the totality of the data for targeted temperature management. And I think, the main thing you say, walking away from this, is avoid fever. Don't let your patients get hot. I'm not sure you can say much more than that right now, until we get more data. Dr. Greg Hundley: Very nice. Well listeners, a really interesting provocative discussion today. And we want to thank Dr. Kevin Roedl from Hamburg, Germany, Dr. Sebastian Wolfrum from Lubeck, Germany, and our own associate editor, Dr. Mark Link from Dallas, Texas, bringing us the results of this study highlighting that hypothermic temperature control is compared with normothermia did not improve survival, nor functional outcome, at 180 days in patients presenting with coma after in-hospital cardiac arrest. Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week On The Run. This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.

Led by her belief that it is never too late to reinvent yourself, Dr. Zhu Shen pivoted from a successful career in biotech to a successful venture into filmmaking. Motivated by her son's extraordinary talents and her husband's life story, Zhu's journey of triumph, heartbreak, and motherhood is fueled by a deep love for her family and her passion for helping others by sharing her stories.  Zhu is a biotech CEO turned award-winning filmmaker best known for two Oscar-qualified critically acclaimed animation shorts. She produced Ingrid Pitt: Beyond the Forest about a young Holocaust survivor animated by her 11-year-old son, Perry Chen, and Changyou's Journey about her late husband's life, written and directed by Perry Chen. She is currently writing, directing, and producing her personal documentary feature, Journey of a Thousand Miles endorsed by Janet Yang, President of the Academy of Motion Pictures.  Changyou's Journey premiered at Toronto International Film Festival, screened at 19 International film festivals, and won five US film festival awards. Ingrid Pitt: Beyond the Forest won 3 US film Festival awards and screened at over 30 international film festivals. Zhu's love for movies started while watching propaganda films in her childhood during the Chinese cultural revolution. In her former life, she was an award-winning biotech executive author, speaker, and Chinese business expert, featured on national and trade media, including Fox Business Week, China Central Television, Pharmaceutical Executive, and The Scientist magazine. She earned her Ph.D. in biochemistry from the University of Colorado, her MBA at Cornell University Johnson School of Management, and studied medicine at Peking Union Medical College and pre-med at Peking University. What You Will Hear in This Episode:  How Zhu arrived to where she is today The benefit of dual degrees in science and business First self-manifested opportunity to write Encouraging her son to write film reviews at an early age Becoming an accidental filmmaker Zhu's husband's cancer diagnosis and her son's desire to animate his father's story, Changyou's Journey, inspired Zhu's film, The Journey of a Thousand Miles Lessons learned Helping families reconnect Message for women Quotes “What I did that was successful was to create a niche for myself where I could truly shine and I could leverage my unique knowledge and connections and seize the opportunity to share something that is really exciting with the world.” “That is really the most important thing and what compels me to want to finish this film because I want to share our distinct but also universal journey of how we connected in the end to achieve this level of relationship that is unconditional love that I hope all families could enjoy.” “The film is really a vehicle for sharing our story and journey in the hope of being able to give some food for thought for those who are in the same boat.” “It's never too late to reinvent and guided by your curiosity and passion learn something entirely new." "Your life can be your art and your art can be your life so  there is no reason for us not to live the life that we imagine." Mentioned: Journey of 1000 Miles Film @TigerToZenMom LinkedIn, Facebook, Instagram,  Twitter https://bonniemarcusleadership.com/ https://web.facebook.com/bonnie.marcus/  https://www.linkedin.com/in/bonniemarcus https://twitter.com/selfpromote https://www.instagram.com/self_promote_/ Gendered Ageism Survey Results Forbes article 5 Tips to own the superpower of your age IAMMusicGroup Purchase my book Not Done Yet on Amazon:  If you enjoyed this episode of Badass Women Podcast, then make sure to subscribe to the podcast and drop us a five-star review.

英语新闻︱九价HPV疫苗接种年龄放宽China's top drug regulator has expanded the use of an imported vaccine against nine strains of the cancer-causing human papillomavirus to girls as young as nine and adults up to age 45.近日，九价人乳头瘤病毒疫苗（酿酒酵母），也称九价HPV疫苗，获得中国国家药品监督管理局批准，适用接种人群拓展至9-45岁适龄女性。While hailing the decision as part of China's endeavor to accelerate elimination of cervical cancer, experts said that given the tight supply of the 9-valent vaccine and increasing evidence of the efficacy of homegrown vaccines, it is wise to receive any approved HPV vaccines available.专家称赞此举彰显了中国加速消除宫颈癌的决心。鉴于九价HPV疫苗一针难求，且国产HPV疫苗也能有效预防宫颈癌，因而接种任一获批HPV疫苗都是明智之举。The National Medical Products Administration first granted authorization to Gardasil 9, a 9-valent HPV vaccine created by global pharmaceutical giant Merck, for use in females aged 16 to 26 in 2018. On Tuesday, the administration said that its use is now broadened to females aged 9 through 45.2018年，药企默沙东研发的九价HPV疫苗“佳达修9”首次获批用于16岁至26岁的女性。8月30日，国家药品监督管理局宣布该疫苗适用接种人群拓展至9岁至45岁的适龄女性。Currently, three imported HPV vaccines and two domestic vaccines have been approved for use on the mainland. Gardasil 9 is the only one that can shield nine strains of HPV, while the others offer protection against either two or four strains.目前我国已有五款HPV疫苗获批注册，包含了三款进口HPV疫苗和两款国产疫苗。“佳达修9”是唯一能够预防九种HPV病毒类型的疫苗，而其他疫苗则可以抵御两种或四种HPV病毒类型。Qiao Youlin, a professor at the School of Population Medicine and Public Health at the Peking Union Medical College, said that HPV vaccines work best among teenage girls and those who have not had a sexual encounter, but sexually active women can still benefit from getting vaccinated.中国医学科学院北京协和医学院群医学及公共卫生学院乔友林教授指出，青少年女孩接种HPV疫苗，容易激发更好的免疫反应，未发生性行为的女性接种HPV疫苗将获得最佳预防效果。"Expanding the age group eligible for the 9-valent vaccine will offer more options for Chinese females of different ages to prevent HPV infection and protect their health, and advance China's action to accelerate the elimination of cervical cancer," he said in a news release published by Merck on Tuesday.8月30日，乔友林教授在默沙东公众号发布的文章中表示：“九价HPV疫苗获批扩龄更是令我们倍感振奋，其将为我国不同年龄层的女性预防HPV感染和降低相关疾病风险带来更多守护健康的选择，并进一步推动我国加快消除宫颈癌的步伐。”In China, nearly 110,000 women were diagnosed with cervical cancer last year, and 59,000 had died of the disease, said Zhao Fanghui, a professor at the National Cancer Center and Chinese Academy of Medical Sciences' Cancer Hospital, citing data from the Global Cancer Observatory, a cancer data platform associated with the World Health Organization.国家癌症中心、中国医学科学院肿瘤医院的赵方辉教授援引世界卫生组织国际癌症研究机构的数据称，2020年我国宫颈癌新发病例约11万，死亡病例约5.9万。"Official data also show that the incidence of cervical cancer in China is rising and the average age of patients is getting younger, which is highly concerning," she said.赵方辉说：“官方数据显示，我国宫颈癌呈现发病率上升、发病年轻化的趋势，这是非常令人担忧的。”Eliminating the disease would require consolidated efforts in boosting the vaccination rate, especially among those aged under 15, as well as promoting early screening and treatment. Due to limited supplies and low awareness, China is now lagging far behind some leading countries in terms of immunization coverage, according to Zhao.赵方辉表示，消除宫颈癌还需加强努力，提高疫苗接种率，尤其是15岁以下人群的接种率，促进癌症筛查和早诊早治。由于HPV疫苗供应有限，公众认知不高，中国目前的疫苗覆盖率仍处于较低水平。However, the rising number of highly effective domestic vaccines available on the market is expected to ramp up the efforts.不过，具有高保护效力的国产HPV疫苗数量逐年增加，为中国宫颈癌防治事业增添了新动力。Six homegrown 9-valent HPV vaccines have entered the third stage of clinical trials, according to information shared by Dong Shaozhong, a researcher at Walvax Biotechnology, during a forum held during the weekend. Doses that protect against even more strains are also under research.沃森生物研究员董少忠表示，6种国产九价HPV疫苗已经进入Ⅲ期临床试验阶段，预防更多HPV病毒类型的疫苗也在研发中。Even though the highly-coveted 9-valent vaccine is not easily available at present, Zhao said unvaccinated groups should not hesitate to receive a dose that protects against two strains.赵方辉表示，九价HPV疫苗一针难求，适龄女性不必盲目等待高价次疫苗，可尽早接种二价HPV疫苗。A new study published in the journal The Lancet Infectious Disease on Friday shows that Cecolin, the first domestic vaccine that protects against two HPV strains, is 100 percent effective in protecting against genital lesions－a precancerous condition－and 97.3 percent effective against persistent infection.8月26日，《柳叶刀-感染病学》发表的一项新研究表明，国产HPV疫苗馨可宁可有效预防HPV16型和18型病毒类型，对HPV16型和/或18型感染相关的病变终点的保护率为100.0%，对HPV16型和/或18型持续性感染（6月以上）的保护率为97.3%。Zhao, who is involved in the study, said the data shows that the domestic vaccine's efficacy is on par with its international alternatives.参与此项研究的赵方辉教授表示，数据显示，国产疫苗与进口疫苗的疗效不相上下。Moreover, the two types of HPV that the vaccine is capable of protecting against cause about 84.5 percent of cervical squamous cancer cases－the most common form of cervical cancer－in China, higher than the global average of 70 percent.馨可宁能够预防约84.5%的宫颈癌鳞癌病例，宫颈癌鳞癌是我国宫颈癌当中最为常见的类型，发病率高于全球平均水平七成。"The follow-up study that tracks more than 7,300 women for about 5.5 years adds evidence to the long-term protection provided by the domestic vaccine," she said. "It can also inform the formulation of public health policies and boost public confidence in and acceptance of domestic vaccines," she said.赵方辉介绍说：“研究团队对7300多名志愿者进行了为期5年半的随访，为国产疫苗的高保护率提供了数据支撑”赵方辉说道：“研究结果为公共卫生政策的制定提供了必要信息，还有利于提高公众对国产疫苗的信心与接受度。”While the latest authorization for Gardasil 9 means that more well-off groups can access the vaccine, Zhao suggested the general public not hesitate to receive available vaccines as soon as possible.虽然“佳达修9”接种年龄放宽意味着更多富人能够打上疫苗，但赵方辉建议公众不必执着高价数疫苗，及早接种疫苗。记者：王小予cervical英[ˈsɜ:vɪkl]；美[ˈsɜrvɪkl]adj. [解]颈的;子宫颈的shield英[ʃiːld]；美[ʃiːld]vt.保护;掩护;庇护;给…加防护罩n.盾;护罩;盾形奖牌;保护人eligible英[ˈelɪdʒəbl]；美[ˈelɪdʒəbl]adj.有资格的;（作为结婚对象）合适的alternative英[ɔːlˈtɜːnətɪv]；美[ɔːlˈtɜːrnətɪv]n. 可供选择的事物adj.替代的，备选的;另类的

In a move to safeguard patients' right to die, China's southern tech hub Shenzhen has become the country's first city to pass legislation on living wills, requiring hospitals to respect critically ill patients' wishes on whether to continue medical treatments. Why is there a need to make it into law? What has been preventing average Chinese from signing living wills? Does it signal a first step towards legalizing euthanasia in China? Host Tu Yun is joined by Nadia Chun-yueh Chen, Member of Board of Directors, China Will Registration Center, Professor Wang Chenguang, Tsinghua Law School & Vanke School of Public Health, and Dr. Zhang Di, Associated Professor, Peking Union Medical College & Chinese Academy of Medical Sciences on this episode of Chat Lounge.

Photo:  The Peking Union Medical College was founded in 1906 by the American and British missionaries and funded by the Rockefeller Foundation. It remains one of the finest medical schools in China today. Not clear if it participates at all in organ theft. 2/2:  #PRC: Data evidence of murder by organ harvesting. Matthew Robertson @WSJOpinion; research Fellow at the Victims of Communism Memorial Foundation. https://www.wsj.com/articles/china-new-evidence-surgeon-doctor-execution-murder-prisoner-organ-harvesting-donor-uyghur-falun-gong-genocide-human-rights-world-health-organization-who-11654012796

How do we live our lives when the heartbreakingly unthinkable happens - the loss of a young husband and father? If you are Zhu Shen and her son Perry, you 'take your broken heart and make it into art.' as the late Carrie Fisher counseled.Today on Embark, we talk about life, loss, the nature of art as both healing mechanism and lasting tribute to our loved ones who have left us. You can watch and support Zhu's films here   for exclusive screening invitations and major updates, and receive FREE link to watch Zhu and Perry's  Oscar-qualified Changyou's Journey:Listeners of Embark can watch exclusive scenes from our documentary feature in late production from now till March 20, 2022 HERE:BiographyDr. Zhu Shen is an award-winning film producer, best known for two Oscar-qualified, critically acclaimed animation shorts she produced: Ingrid Pitt: Beyond the Forest about a young Holocaust survivor, animated by her 11-year-old son Perry Chen in 2011, and Changyou's Journey about her late husband's life, written and directed by Perry Chen in 2018. She is currently writing, directing, and producing her first feature film, a personal documentary, Journey of a Thousand Miles. A 2020 Spring Roy Dean Grant Finalist. A former award-winning biotech executive, author, speaker and China business expert,  Shen's love for movies started when she grew up during the Chinese Cultural Revolution and movies were the only available  mass entertainment.  Zhu Shen's work has featured on national and trade media including Fox, Business Week, China Central Television, Pharmaceutical Executive, and the Scientist Magazine. She earned her Ph.D. in biochemistry from University of Colorado, her MBA at Cornell University Johnson School of Management, studied medicine at Peking Union Medical College, and pre-med at Peking University. Social Media Links: LinkedInFacebookInstagramTwitterDr. Zhu Shen is an award-winning film producer, best known for two Oscar-qualified, critically acclaimed animation shorts she produced: Ingrid Pitt: Beyond the Forest about a young Holocaust survivor, animated by her 11-year-old son Perry Chen in 2011, and Changyou's Journey about her late husband's life, written and directed by Perry Chen in 2018. She is currently writing, directing, and producing her first feature film, a personal documentary, Journey of a Thousand Miles. A 2020 Spring Roy Dean Grant Finalist. A former award-winning biotech executive, author, speaker and China business expert,  Shen's love for movies started when she grew up during the Chinese Cultural Revolution and movies were the only available  mass entertainment.  Zhu Shen's work has featured on national and trade media including Fox, Business Week, China Central Television, Pharmaceutical Executive, and the Scientist Magazine. She earned her Ph.D. in biochemistry from University of Colorado, her MBA at Cornell University Johnson Sch

Please join author David Webb and Editorialist Steven Smith as they discuss the original research article “Regular Acetaminophen Use and Blood Pressure in People With Hypertension: The PATH-BP Trial" and the editorial "Acetaminophen-Induced Hypertension: Where Have All the "Safe" Analgesics Gone?" Dr. Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm your host today, Dr. Carolyn Lam, associate editor from The National Heart Center in Duke National University of Singapore. And I'm so missing my co-host Dr. Greg Hundley, who can't make it today, but will be back next week. Now, I have the privilege of telling you all about the exciting papers in today's issue, but before I even get there, I need to let you know that coming right up is a discussion you are not going to want to miss. It deals with an issue that we encounter very commonly and perhaps should have questioned many times, but haven't yet. What is it? Well, regular acetaminophen use and its blood pressure effect. Acetaminophen, what we commonly call paracetamol or Tylenol depending where you're coming from, but have we ever stopped to really ask, does this impact blood pressure? We're going to find out more in the path BP trial coming right up, but first here are your summaries. Dr. Carolyn Lam: The first original paper I'd like to tell you about is a study representing additional four years a follow up from the Danish trial. Now recall that Danish was a trial that found that primary prevention ICD implantation was not associated with an overall survival benefit in patients with non-ischemic systolic heart failure, doing a median follow-up of 5.6 years. Although, there was a beneficial effect on all-cause mortality in patients aged 70 years or younger. Now, the current study led by Dr. Lars Køber from Copenhagen University Hospital and colleagues showed that during a median follow up of now 9.5 years, ICD implantation did not provide an overall survival benefit in patients with non-ischemic systolic heart failure. In patients age 70 years or younger, however, ICD implantation was associated with a lower incidence of all-cause mortality, cardiovascular death, and sudden cardiovascular death. Dr. Carolyn Lam: The next original paper reports on pre-specified analyses from the FIGARO-DKD trial assessing the impact of finerenone known on clinically important heart failure outcomes. Now recall that FIDELIO-DKD and FIGARO-DKD, in those trials finerenone, which is a selective nonsteroidal mineralocorticoid receptor antagonist, improved cardiovascular outcomes in patients with albuminuric chronic kidney disease and type two diabetes. In the current study, Dr. Filippatos from Attikon University Hospital in Athens, Greece and colleagues presented the pre-specified analyses of FIGARO-DKD describing novel heart failure related outcomes, which were not previously published in finerenone studies, and these included new onset heart failure. Different outcomes containing first or total hospitalization for heart failure events in the overall population. The results indicated that in patients with chronic kidney disease and type two diabetes on a maximum tolerated dose of renin-angiotensin system inhibitor therapy, fenerenone reduced new onset heart failure and improved heart failure related outcomes irrespective of history of heart failure. This is the first indication that a nonsteroidal mineralocorticoid receptor antagonist may provide benefit in a population with chronic kidney disease and type two diabetes, in which patients with heart failure with reduced dejection fraction or symptomatic NYHA 2-4 were excluded, thus indicating that patients with type two diabetes and chronic kidney disease at risk of heart failure or with early stage heart failure may indeed benefit from fenerenone treatment. Dr. Carolyn Lam: The next original paper shows for the first time, a role of the nuclear receptor Rev-Erb, a key component of the circadian clock in obesity. So, co-corresponding authors, Dr. Song from Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China, as well as Doctors Zheng Sun, both from Baylor College of Medicine, and their colleagues used mice with cardiomyocyte specific Rev-Erb deletion that manifested contractile dysfunction, cardiac dilatation, and heart failure. And using these models, authors showed that there was a temporal coordination between clock mediated anticipation and nutrient induced response in myocardial metabolism at multiomic levels. Obesity, together with insulin resistance via a high fat diet, paradoxically improved dysfunction and fatty acid availability from edibles lipolysis in the disrupted circadian mouse model that Rev-Erb knockout. These elegant studies reveal a punitive link between circadian regulation and nutrient induced responses in the heart, potentially helping to explain the obesity paradox. Cardiac molecular chronotropes may, therefore, be involved in human dilated cardiomyopathy. And the implication is that myocardial bioenergetics downstream of Rev-Erb may be a chronotherapy target in treating patients with heart failure. Now, all of this is discussed in an editorial by Dr. Inna Rabinovich-Nikitin and Dr. Lorrie Kirshenbaum from Manitoba, Canada. Dr. Carolyn Lam: The final original paper in today's issue is an important translational paper, in which ZEB2, which is a master regulator of epithelial to mesenchymal transition and is associated with many cancers, has for the first time been identified as a new coronary artery disease associated gene. This was first identified by human Genome-wide Association studies, following which the authors Dr. Quertermous from Cardiovascular Institute Stanford and colleagues used smooth muscle cell specific deletion of ZEB2 in mice, coupled with single cell transcriptomic and epigenetic profiling of smooth muscle cells specific [inaudible 00:07:31] cells, and showed that ZEB2 dramatically alters cell state trajectories of the smooth muscle cells through epigenetic regulation of TGF-β and notch signaling. Lower ZEB2 in smooth muscle cells resulted in atherosclerotic plaques with high risk features. So what are the clinical implications? Well, therapies that specifically regulate smooth muscle behavior can potentially alter the risk of plaque rupture, and may be used to further reduce the risk of myocardial infarction. Existing chemotherapies and additional drugs in development that modulate the epigenetic silencing, such as HDAC inhibitors or hypomethylating agents, may, on the other hand, increase the risk of myocardial infarction. Dr. Carolyn Lam: So very interesting paper. Wraps it up for our original papers, and now onto what else there is in today's issue. There's an On My Mind paper by Dr. Messerli on [entitled] “Why Are We Still Prescribing ACE Inhibitors?” and a Research Letter by Dr. Simon on one-year major cardiovascular events after restrictive versus liberal blood transfusion strategy in patients with AMI and anemia from the reality randomized trial. Well, that's it for the summaries. Thanks for joining. And please hang on tight for this next exciting feature discussion. Dr. Carolyn Lam: For today's feature paper, we are talking about a very familiar medication. Believe it or not, it's just paracetamol, or acetaminophen in its generic term. What we also call Tylenol in the US. And I'm sure this is something that everybody recognizes as one of the first line therapies that we take for chronic pain. It's even over the counter. It's perceived as extremely safe, and in particular, is as having little or no effect on blood pressure. But is that correct? Ah, this paper, I have to tell you audience, really sent chills up my spine. I learned so much from it and I am so, so pleased to have with us the corresponding author, Dr. David Webb from Queens Medical Research Institute in Edinburgh, as well as our editorialists Dr. Steven Smith from University of Florida in United States to discuss this very, very important paper. David, if you don't mind if I start with you, what made you look at this question? It's strikingly important, but seemingly strikingly ignored until your study, so please tell us about that. Dr. David Webb: So paracetamol, or acetaminophen, has a really long history going back to the 1800s, and it replaced a drug that was removed called phenacetin that caused significant toxicity. It didn't really grow in use until about the 1980s, but from then on, it really took off and now it's the most widely used and prescribed analgesic in the world. There have been observational studies, large ones, and small clinical trials that suggested an increase in blood pressure. We undertook a systematic review in 2013 that suggested this really needed to be a topic for a further study, and so we undertook a randomized control trial to answer the question of whether, in hypertensive subjects, paracetamol would increase blood pressure. Dr. Carolyn Lam: Well, thank you for that background. I have to admit, I didn't even know about the origins and that very first paper you talked about, and this is really beautifully summarized as well in, Steve, your beautiful editorial. But before we go there, David, could you tell us about this path BP trial, what you did and what you found? Dr. David Webb: So we were funded by the British Heart Foundation, and we under took a randomized placebo controlled blinded study of one gram of paracetamol given four times a day versus match placebo. And we looked primarily at the gold standard ambulatory blood pressure in patients with hypertension, a third off treatment, and two thirds on treatment, and about a hundred, more than a hundred patients took part in this study. It was a crossover study with washout, and we saw that ambulatory blood pressure compared to placebo treatment increased by five millimeters of mercury, which is substantial. It's very similar to what we see with the nonsteroidal anti-inflammatory drugs, the NSAIDs, which also have effects mediated through prostaglandin metabolism, and that increase of five millimeters of mercury would amount to an increased cardiovascular risk, if sustained, of around 20%. Our study was only for two weeks for practical reasons, but we have no reason to think the effect would not last longer. Dr. Carolyn Lam: And David, just before we carry on, could you clarify a few things? So, these patients did not have pain to enter, and did they have hypertension, and were they on other medications for hypertension? Dr. David Webb: Yeah, so they were patients with hypertension. They had to have an entry average ambulatory blood pressure daytime of more than 135 over 85, but less than 150 over 95, so this is mild to moderate hypertension. A third of them were not treated at the time of the study, but went on to treatment, and two thirds were already on treatment and stayed on their existing treatment. So this is a study in both treated and untreated hypertension, and we saw, although it wasn't powered to look at differences, we saw similar effects in those who were treated and untreated. Dr. Carolyn Lam: So an incredibly important question and Dr. Smith, Steve if I may, you wrote very nicely how the fact that this is individuals with hypertension, but not having an indication of pain and so on. It's really something we needed to look at this question because pain can confound, I suppose, the measurement of blood pressure and so on. So could you tell us a little bit more of why this study is so important and what do you think its impact of the findings will be? Dr. Steven Smith: Sure. Thank you, Carolyn. And first of all, I just say, I appreciate you having me on and getting to discuss this really interesting study by Dr. Webb and his team. I think it's a really interesting study. As you may know now, acetaminophen has been associated with blood pressure increases going back almost half a century now and there have been a number of studies, not all have been particularly strong studies and there's a number of limitations to that literature, and I think I was really fascinated by Dr. Webb's study because they really just asked a simple question and did a well designed, robust study to try to address that question and I think it provided some pretty definitive results. Dr. Steven Smith: As I mentioned in the editorial, despite the fact that acetaminophen has been associated with blood pressure increases in the past, if you go look at Google or whatever, your favorite search engine of choices, you'll find a number of articles right at the top that seem to imply or directly state that acetaminophen is perfectly safe for patients with high blood pressure. And I think that's a concerning thing that the medical information out there is implying or directly stating that acetaminophen is perfectly fine for these patients and so, I'm appreciative with the work that Dr. Webb is doing to try to bring to light some of the risks of acetaminophen Dr. Carolyn Lam: Indeed. And I think it raises a lot of questions that you also so nicely put in your editorial, and maybe this is the chance to ask David directly. For example, what do you think are the implications, in terms of generalizability, in chronic uses of acetaminophen in lower or higher doses in people without hypertension? I mean, this is a big and important issue. What do you think, David? Dr. David Webb: Sorry, Carolyn. Maybe I could start by just sticking to the subjects of the study itself. I think what this tells us, and it's important to recognize that there is very little evidence that paracetamol provides benefit in chronic pain. It's not of any value in low back pain. There seems to be no evidence that it's particularly useful in cancer pain and in a wide range of other forms of pain. The evidence for benefit is very limited, so harms really matter where the benefit is small, and probably most patients with chronic pain are not benefiting from the paracetamol in terms of its analgesic effect. So cautiously trying to withdraw treatment in these patients may well be a benefit in terms of reducing cardiovascular risk. So that's for what patients with hypertension. So beyond hypertension, that's a bit more difficult because we didn't study that, but we looked at a range of blood pressures. Dr. David Webb: And whilst we weren't powered to address this specifically, it looks as though the effects are there for lower blood pressures and for higher blood pressures. So, it would be nice to do the direct study, but it looks as though this might be slightly more general I support. We didn't look at people with chronic pain for practical reasons, but as I say, there's very little evidence that paracetamol is providing a benefit. I always thought that paracetamol was a safe drug. I use it in my hypertension clinic. And I think in my head, this is safer than using a nonsteroidal, but they're less effective and they may be no safer. So I think one needs to inform clinicians and their patients about the relative safety of paracetamol when considering treatment for chronic pain. You asked one other question. In the UK four grams a day as a common dose. It is in many parts of the world as a maximum dose. In the US, FDA has advised reducing to three grams a day as the maximum dose. You can still give four grams a day, but I think that's a helpful recommendation because this is very likely to be a dose dependent effect. So the lower maximum dose will to some extent protect subjects. Dr. Carolyn Lam: And Steve, would you agree with that? What would your take-home message to the audience be, or what do you think are the most important unanswered questions? Dr. Steven Smith: Yeah, it's a great question. If I could piggyback on David's answer, I think one of the really interesting findings from this study is that we see these blood pressure changes even after only two weeks of therapy, so this is not something that requires some chronic, very high dose of acetaminophen to start experiencing these blood pressure changes. Obviously a lot of people are on acetaminophen, as David mentioned all over the world. Many of those patients, of course, are on it for chronic therapy, for example, for osteoarthritis, but a lot take it much more sporadically or for short term use. And I think it's telling that we see these blood pressure changes pretty rapidly after starting therapy. Dr. Steven Smith: As far as unanswered questions go, I think Dr. Webb summarized some of those already, but I guess what I would add is we still lack some clarity on what the ultimate outcomes of these blood pressure changes are. Obviously we know that blood pressure is highly correlated with adverse cardiovascular outcomes, as well as other outcomes, but the data showing an increased cardiovascular risk with acetaminophen is a little bit more murky. And so I do think there's still some question as to how this translates to increased cardiovascular risk, and I totally agree with David that the evidence supporting efficacy of acetaminophen is so weak at this point for most things, it may be a moot point. We may want to just move on from acetaminophen to the extent that we can, because it seems to have some risks, or at least some concern for risks, without a lot of evidence. Dr. Carolyn Lam: Wow. Thank you so much, gentlemen, for this. It's just amazing discussion, but even more so for publishing such an important study and such an elegant editorial in our journal. I think this is one that not only may change practice, but changes my personal perception and things that I'm going to do immediately. Dr. Carolyn Lam: Thank you very much audience. I'm sure you agree. This was incredible. Do tune in again next week for another episode of Circulation On The Run. Dr. Greg Hundley: This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week’s episode includes author Charlotte Andersson and Associate Editor Naveed Sattar as they discuss familial clustering of aortic size, aneurysms, and dissections in the community. TRANSCRIPT: 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, director of the Pauley Heart Center at VCU health in Richmond, Virginia. Well, Carolyn, our feature this week has to do with aortic size, aneurysms, and predilection to dissection. But before we get to that, how about if we grab a cup of coffee and go through some of the other articles in the issue? Dr Carolyn Lam: I got my coffee, Greg, and you know what? I'm going to start with quiz for you. Dr Greg Hundley: All right. Dr Carolyn Lam:  True or false, in the setting of obesity and/or diabetes, cardiac substrate metabolism shifts towards increased fatty acid oxidation, while lipid accumulates in the heart? True or false? Of course, you're right. Oh, but there's a part two. Can you guess, by increasing fatty acid oxidation, will we induce or prevent obesity-induced lipotoxic cardiomyopathy? Dr Greg Hundley: I'm going to say, because you asked it in the way you asked it, prevent. Dr Carolyn Lam: Wow. All right. Well, the truth is we didn't really know before today's paper. The specific link between cardiac metabolism and lipotoxic cardiomyopathy was elusive and there was no specific therapy available for this condition. And these authors, Dr Rong Tian from University of Washington and colleagues, hypothesized that cardiac pathology-associated obesity would be attributable to the imbalance of fatty acid supply and oxidation. So using a diet-induced obesity model in the current study, they demonstrated that enhancing fatty acid oxidation through deletion of acetyl-CoA carboxylase 2, was sufficient to prevent obesity-induced cardiomyopathy. So, increasing cardiac fatty acid oxidation alone does not cause cardiac dysfunction, but instead protects against cardiomyopathy in chronically obese mice. The cardiac-protective effect of increasing fatty acid oxidation and obese mice is through maintenance of Parkin-mediated mitophagy, and thus preventing mitochondrial dysfunction. These findings indicate that impaired mitophagy contributes to mitochondrial dysfunction in obese mice, and that targeting the Parkin-dependent pathway is a viable therapeutic intervention for obesity-induced cardiomyopathy. Dr Greg Hundley: Very nice. Carolyn. Dr Carolyn Lam: I'm going to be greedy and go on to my next paper. So Greg, do you think cardiac regeneration is possible? Dr Greg Hundley: Well, Carolyn, I would have said, several years ago, no, but that trip that we took to China with Joe Hill and Hesham Sadek, our Associate Editor and our Chief Editor, convinced me otherwise. So I'm going to definitely answer yes on this one. Dr Carolyn Lam: Oh, Greg, you're just too smart. And speaking of China, this next paper is from there, from co-corresponding authors, Dr Nie and Hu, from Fuwai Hospital National Center for Cardiovascular Disease and Chinese Academy of Medical Sciences and Peking Union Medical College. So, using seven genetic mouse lines, they identify that Oncostatin M is the top upregulated cytokine during neonatal heart regeneration. Oncostatin M is a pleiotropic secretory protein that belongs to the interleukin 6 family, and associates with the pathological process of dilated cardiomyopathy. And these authors found that macrophages promote heart regeneration by secreting Oncostatin M, which promotes cardiomyocyte proliferation via a co-receptor, gp130. Employing RNA-seq and functional screening, they further found that Src-mediated gp130 triggered cardiomyocyte proliferation by activating the downstream signaling pathway involving Yap, with Y357 phosphorylation independent of the Hippo pathway. So the last thing that they did was show that gene therapy with adenovirus-associated virus and coding this activated gp130 improved heart regeneration and pumping function, thus serving as a potential therapeutic target. An amazing paper. Dr Greg Hundley: Very nice, Carolyn. What a great summary and so much detail. Well, Carolyn, I'm going to turn our attention to catecholaminergic polymorphic ventricular tachycardia. And this article comes to us from Dr Jason Roberts, from the Western University. Carolyn, genetic variants in calsequestrin 2 can cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia, though isolated reports have identified arrhythmogenic phenotypes among heterozygotes. So in this study, a total of 112 individuals, including 36 catecholaminergic polymorphic ventricular tachycardia probands, 24 were homozygotes for compound heterozygotes, and 12 were pure heterozygotes, against 76 family members possessing at least one presumed pathogenic calsequestrin 2 variant. These were all identified. Dr Carolyn Lam: Wow, a very precious cohort. So what did they find, Greg? Dr Greg Hundley: This international multicenter study of calsequestrin 2 catecholaminergic polymorphic ventricular tachycardia really redefined its heritability and confirmed that pathogenic heterozygous calsequestrin 2 variants may manifest with a catecholaminergic polymorphic ventricular tachycardia phenotype, indicating a need to clinically screen these individuals. Among individuals heterozygous for a pathogenic calsequestrin 2 rare variant, medical therapy and exercise restriction are likely not necessary in the absence of the catecholaminergic polymorphic ventricular tachycardia phenotype. Though, you have to be certain over time, an intermittent clinical screening to ensure they remain phenotype-negative should be obtained. Dr Carolyn Lam: Wow, Greg, clinically important study there. Well, I'm going to go back to the basic science world and talk about calcineurin. Now, calcineurin has long been implicated in the induction of pathological cardiac remodeling but has not been therapeutically targetable for the prevention of heart failure because of its pleiotropy and our lack of understanding of its specific protein-protein interactions and compartmentation within the cardiomyocyte. Dr Greg Hundley: Okay. Carolyn, do you want me to give background on calcineurin? Dr Carolyn Lam: No, Greg, you're off the hook. I'm going to give you some background on calcineurin. So, calcineurin is the calcium-calmodulin-dependent phosphatase that exists as a heterodimer, consisting of a catalytic subunit and a regulatory subunit. Now, of the three catalytic subunit isoforms, alpha, beta, gamma, it's the beta isoform that appears to be the most important for the development of cardiac hypertrophy. Binding of calcium to the calcineurin regulatory subunit enables binding of the calcium-calmodulin complex, thereby releasing auto-inhibition and freeing the enzyme to dephosphorylate downstream substrates. That's the background. Now, in today's issue, we have this great paper from co-corresponding authors, Dr Kapiloff from Stanford University, and Dr Nikolaev from University Medical Center Hamburg. And, with their colleagues, they described the discovery of a calcineurin catalytic subunit beta binding protein Cdc42-interacting proteins 4, and I'm going to call that CIP4, which functions as a scaffold to sequester the pool of calcineurin near the sarcolemma of cardiomyocytes, where it regulates pro-hypertrophic signaling. These findings have really important implications for understanding how cardiac calcineurin is selectively activated by stress signals, as opposed to the pleiotropic second messenger, calcium, that really floods the cardiomyocytes during each contractile cycle. Furthermore, the data provide proof of concept for an innovative therapeutic approach, whereby CIP4-anchoring activity is selectively inhibited to block the action of a small pathogenic pool of calcineurin as a means of treating heart failure. How about that? This is really discussed in an elegant editorial by doctors, Woulfe, Travers, and McKinsey. Dr Greg Hundley: Very interesting, Carolyn. Sounds like another possibility for treating and managing heart failure. Well, let me share with you some of the other findings in our mailbag this week. First, I've got, from Professor Lang Li and Stephen Wiviott, they swap research correspondence regarding the prior publication entitled, Effect of Dapagliflozin on Atrial Fibrillation in Patients with Type 2 Diabetes Mellitus, Insights from the DECLARE-TIMI 58 Trial. And then Professor Laszlo Littmann has a nice ECG challenge for us related to a high-risk ECG that exposed some downstream worrisome vital signs. Dr Carolyn Lam: In addition, there's a perspective piece by Dr Nambi discussing the fact that a zero-calcium score is desirable, but isn't enough to defer therapy, given that up to one-third of events will occur in this group. There's also an In Depth paper by Dr Borlaug, entitled, “Altered Hemodynamics and End Organ Damage in Heart Failure, The Impact on the Lung and Kidney,” and oh boy, this one is so beautifully illustrated. Just a must read for the understanding of the hemodynamics in the lung and kidney and heart failure. Next is a research letter by Dr Loeys on enrichment of rare variants in the Loeys-Dietz syndrome genes in spontaneous coronary artery dissection, and not in severe fibromuscular dysplasia. And finally, another research letter by Dr Arora on racial differences in serial NT-proBNP levels in heart failure management with insights from the GUIDE-IT Trial. What a rich issue, but let's move on to our future discussion, shall we? Dr Greg Hundley: You bet, Carolyn. Well, listeners, we're now getting to our feature discussion and it's very interesting this week where we're going to evaluate aortic aneurysms. And we have with us one of the lead authors of this paper, Dr Charlotte Andersson from Boston Medical Center, and our own Associate Editor, Naveed Sattar from Glasgow, Scotland. Charlotte, welcome to our feature discussion. Could you tell us a little bit about the background and the hypothesis that you put forward with this study? Dr Charlotte Andersson: The background for this study was based on clinical work and what we observed in clinic. We had a few patients where we had been stricken by the fact that they came in with an acute aortic syndrome and they had a first-degree relative themself with the condition, but they did not look syndromic at all. And we started to wonder, what is the actual risk in the community, in people without obvious syndromic features of suffering from an aortic event itself. And although there are quite a few studies out there that have, to some degree, focused on the familial clustering of aortopathies, there is not a lot of information based on communities and whole entire populations. So we wanted to, frankly, estimate what is the incidence rates of aortic dissections and aortic aneurism in the community if you have a first-degree relative that has suffered from the disease themselves. Dr Greg Hundley: How you organize your study and what was your population and what was your design? Dr Charlotte Andersson: This study was actually based on two independent samples. First, we used the Framingham Heart study population that is very densely phenotypes over many years of spanning three generations of participants, where we looked at people who had at least one parent who had an aortic size in the upper quartile index to body-surface area and adjusted for age and sex. And we saw what's the risk of you, as a child, having an aortic size in the same upper quartile. And second, we looked in the general Danish population, the Danish healthcare system is, as you probably know, governmental funded and we have very good registries of all hospitalizations, all outpatient visits, and so we were able to link more hard clinical events in people with and without a first-degree relative. What we did was we started time when people had an aortic dissection, we identified all the first-degree relatives in these people, and we matched them with up to 10 sex and age match controls from the general population without a first-degree relative with the disease. Dr Greg Hundley: What did you find? Dr Charlotte Andersson: We found that in the Framingham sample, if you had at least one parent who belongs into the upper quartile of aortic size, you had an odds ratio of two to three, adjusted for various clinical risk factors, such as hypertension and smoking yourself. And in Danish population, we found that if you had a first-degree relative with an aortopathy, the hazard rates for you developing the disease yourself was almost a tenfold-increase compared to age and sex match controls. And importantly, seemed like hazard ratios use were, more or less, unchanged when we start adjusting various known risk factors, such as bicuspid aortic valve, Marfan syndrome, and Ehlers-Danlos syndrome, normally those kinds of things. And we also found that the younger your proband were at the time of an acute event, the higher was your relative risk yourself. So among people who were below the age of 50 when they suffered an event, the hazard ratios were up to a 50-fold increase. Dr Greg Hundley: Very nice. Naveed, what attracted you to this article as it was coming through the editorial process? And then second, how do we take the information that Charlotte's just conveyed and will be published here today, how do we take this in the context of what we already know about aortic aneurysms? Dr Naveed Sattar: I think it's a beautiful study, so well done, Charlotte. I think it's a beautiful fusion. As Charlotte said, an in-depth cohort study, which has got very well-measured parameters of systematic points and a fantastic population-based data set from Denmark, which Sweden shares and Scotland shares and relatively small countries like us share. So small countries like Denmark punch above their weight in these kinds of studies, which is fantastic. But there's a rich seam of research that comes from these, and this is one of them. So I think that fusion of two data sets with different strengths and limitations combined giving off same signals is good. I think, as Charlotte said, this is the first major population study to look at this question. So there's been people around the world who have got this sense that the aortic aneurism may well be familial, this provides, probably, some of the best data to suggest, yes, it definitely is. Now the questions going forward is, okay, at what point do you screen everybody's got a family history with a proband, or do you screen those who've got a family history of younger probands? And I think what Charlotte and the team and other people around the world thar are going to look at this say, "Okay, we now think, in addition to screening, for example, in the UK and the US we probably screen just men above 65, where most of the disease is, do we also then implement screening in younger people with family histories? And who do we screen, and when and how? And do we need to develop some kind of risk score?" And then when we do that screening, what do we do about it? Is going to be the questions and I'm sure Charlotte and her colleagues have thought about these things and it'd be interesting to see what her view is on those things. But I think it was a beautiful study in every sense. Dr Greg Hundley: So Charlotte, he's really set you up nicely, what study do we need to perform next in this area? What are you and your group thinking about? Dr Charlotte Andersson: Yeah, I think there are two implications of this study. First, clinical, as Naveed says. They already had a sense that aortic diseases were heritable, and I think these data definitely support that we should probably screen first-degree relatives. And I think, at some extent, this is what the guidelines already encourage us to do. So I'm not sure it would be feasible to randomize people or do a clinical trial where we screen some but not others. I'm not sure that would be ethical. I think the evidence is too strong for familial clustering and that we should probably screen these people. But I think also, our estimates, they are so strong that I suspect that there are likely more genetic variants associated with non-syndromic aortopathies that we are not aware of just yet. So I think the next step would be to try to disentangle the genetics a little bit more. I have seen some preliminary analysis based on the UK Biobank, for instance, and I think there are more genetic variants to come up with also, more common genetic variants, at least, that we are not aware of just yet. So that would be the next step as I see it. Dr Naveed Sattar: And that might particularity in younger probands. Dr Charlotte Andersson: Right. Dr Naveed Sattar: Those with the younger probands, because it looks like, as you said, the hazard ratio, the risks, are so high, it could also potentially be monogenic, but anyway. Dr Charlotte Andersson: I agree. Dr Greg Hundley: Well, Charlotte, Naveed, we really appreciate your time and taking this opportunity to discuss these really interesting findings and helping us understand that, truly, there may be a familial component to understanding this disease process, particularly in patients with aortic aneurysms that may go on to develop aortic dissections. Well listeners, we hope you have a great week and on behalf of Carolyn and myself, catch you on The Run next week. This program is copyright, the American Heart Association, 2020.  

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, Director of the Pauley Heart Center from VCU Health in Richmond, Virginia. Dr Carolyn Lam: Our feature paper today discusses trans-ethnic genome-wide association studies and the insights in the genetic architecture and heritability of long QT syndrome, a massive study that we will be digging into, but only after we talk a little bit about the other papers in this week's issue. And I'm going to start, Greg. Are you ready with your coffee? Dr Greg Hundley: I am. Dr Carolyn Lam: The first original paper really represents seminal work, showing that the endothelium can directly regulate obesity and insulin resistance. Now, as obesity develops, there is a decline in adipose tissue vascularity, which seems counterintuitive, and an increase in fibrosis. So authors, led by Dr Chen from the Irell and Manella Graduate School of Biological Sciences in the City of Hope, speculated that the reduction in vascularity in this adipose tissue might have an adverse effect on adipose tissue function. Now, these authors previously identified Argonaute-1, or AG01, a key component of microRNA-induced silencing complex, as a crucial regulator in hypoxia-induced angiogenesis. So in the current study, they aim to determine the AG01-mediated endothelial cell transcriptome, the functional importance of AG01-regulated endothelial function in vivo, and the relevance to adipose tissue function and obesity. A new mouse model with genetic deletion of AG01 in the endothelium was useful to investigate the importance of endothelial regulation of adipose tissue function. The findings were that in mice fed high fat, high sucrose diet, the suppression of endothelial AG01 promoted adipose tissue browning, and led to an anti-obesity phenotype. Endothelial cell AG01 thrombospondin-1 pathway was induced in the endothelium from human donors with insulin resistance. In total, this study suggests a novel mechanism, by which endothelial cells through AG01 thrombospondin-1 pathway controls vascularization and function of adipose tissues, insulin sensitivity, and whole-body metabolic state. Dr Greg Hundley: Interesting, Carolyn. So tell me about this clinically. Where do we take this from here? Dr Carolyn Lam: I thought you would ask. So endothelial dysfunction, per se, can cause metabolic dysregulation, rendering targeting dysfunctional endothelium, a potential therapeutic strategy to counteract obesity, and metabolic disorders. So this study really opens a door to that. Dr Greg Hundley: Very nice. Well, I've got another basic science paper, and it evaluates single-cell RNA sequencing to dissect the immunological network of autoimmune myocarditis. And it comes from Dr Jiangping Song from the State Key Laboratory of Cardiovascular Disease of Fuwai Hospital, and the National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, and Peking Union Medical College. So Carolyn, the study aimed to investigate the immunological network during the transition from myocarditis to cardiomyopathy, and to identify the genes contributing to the inflammatory response to myocarditis. So mice were treated with myosin heavy chain alpha-peptides to generate an experimental autoimmune myocarditis model. The investigators performed single-cell RNA sequencing analysis of CD45 plus cells extracted from mouse hearts during different experimental autoimmune myocarditis phases, including normal control, acute inflammation, subacute inflammation, and then in the myopathy phase. Also, human heart tissues were collected from surgically removed hearts of patients who had undergone heart transplantation. Dr Carolyn Lam: So what did they find, Greg? Dr Greg Hundley: Well, Carolyn, a comparison of the single-cell RNA sequencing data from different experimental autoimmune myocarditis phases suggested that some cell clusters, such as macrophage cluster 2 and Th17 cells, were associated with the inflammatory response in the experimental autoimmune myocarditis model. The HIF1A expression level correlated with the extent of the inflammatory response, and PX-478, a HIF1A inhibitor, alleviated the inflammation during the different experimental autoimmune myocarditis phases. Immunohistochemical staining revealed that HIF1A expression was upregulated in autoimmune myocarditis from the tissue samples from the explanted hearts. Thus, the HIF1A inhibitor alleviated inflammatory cell infiltration, and that may serve as a potential therapeutic target in clinical practice. Dr Carolyn Lam: Wow. That is some serious clinical implications. Well, my next paper is really the first systematic echocardiographic evaluation of consecutive patients requiring hospitalization due to COVID-19, and it comes from Dr Topilsky and colleagues from Tel Aviv Medical Center. Dr Greg Hundley: So Carolyn, what did they find in this series? Dr Carolyn Lam: So among a hundred consecutive patients diagnosed with COVID-19 infection who underwent complete echocardiographic evaluation, within 24 hours of admission, only 32% had a normal echocardiogram at baseline. The most frequent abnormality was right ventricular dilatation or dysfunction. Among patients developing clinical deterioration during follow-up, which were 20% of these hospitalized patients, repeated echocardiograms showed further deterioration of the right ventricular parameters, probably related to increased pulmonary resistance. Five of these patients had deep vein thrombosis. Dr Greg Hundley: Carolyn, my next study comes from Dr Stephen Fremes, and it's a modeling study out of the University of Toronto. It modeled TAVR versus SAVR valve durability to determine the effects on life expectancy across a broad range of age. Dr Carolyn Lam: Interesting. And what were the results? Dr Greg Hundley: Well, based on their simulation models, the durability of TAVR valves must be 70% shorter than that of surgically replaced valves to result in reduced life expectancy in patients with similar demographics to recent trials. However, in younger patients, the threshold for TAVR valve durability was substantially higher. In younger patients, life expectancy was reduced when TAVR durability was 30%, 40% and 50% shorter than surgical valves in 40, 50 or 60-year-old patients, respectively. So Carolyn, these findings suggest that durability concerns should not influence the initial treatment decision regarding TAVR versus SAVR in older low-risk patients, based on current evidence supporting TAVR valve durability. However, in younger low-risk patients, valve durability must be weighed against other patient factors, such as life expectancy. Dr Carolyn Lam: Thanks Greg, for that summary. Well, let me tell you about other papers in this issue. There are a pair of letters to the editor by Dr Opotowsky, and a response by Dr Goldberg regarding the paper results of the Fontan Udenafil Exercise Longitudinal, or FUEL trial. There's a research letter by Dr Strik, Validating QT-Interval Measurement Using the Apple Watch ECG to Enable Remote Monitoring During the COVID-19 Pandemic. There are two On My Mind papers, the first, Telemedicine and Forgotten America by Dr Julien, and the second, The COVID-19 Pandemic: Ethical and Scientific Imperatives for "Natural" Experiments by Dr Lewis. Dr Greg Hundley: Very nice. Well, Carolyn, I've got a research letter evaluating the effect of evolocumab on atherogenic lipoproteins during the peri and early post-infarction period. It's a placebo-controlled randomized trial from Dr Gary Gerstenblith. Sarah Cuddy also worked through a tough case of cardiac amyloid when a fat biopsy was negative, but imaging studies of the heart suggested cardiac amyloid. Carolyn, I've also got an On My Mind piece, and it's entitled, Can Old Ally Defeat a New Enemy? And it's by Dr Paul Gurbel, and he discusses the use of inhaled aspirin to treat patients with COVID-19. And then finally, Carolyn, I have a prospective piece from Dr Robert Lefkowitz who discusses β-arrestin-biased angiotensin II receptor agonists for treatment of COVID-19. Well, Carolyn, what a great issue, and let's get onto that feature discussion. Dr Carolyn Lam: Yay. Let's go, Greg. Dr Greg Hundley: Well, listeners. Now we're turning to our feature discussion, and we are very fortunate to have Professor Connie Bezzina from Amsterdam University Medical Center to talk to us about her paper related to long QT syndrome. Welcome, Connie. And I was wondering, before we get started in discussing your paper, could you tell us a little bit about the background in this area? And then, what was the hypothesis that you wanted to address? Prof Connie Bezzina: So over the last 20 to 30 years, we've learned a lot about the genetic underpinnings of inherited cardiac disorders associated with sudden cardiac arrest. And basically, we've learned a lot about mutations in specific genes that co-segregate with these disorders within families. However, two outstanding features have remained unresolved. Essentially, the first unresolved issue is the fact that we observe, oftentimes, a low disease penetrance and variable disease expression within families, which means that not everybody within a family that carries a familial mutation is affected by the disorder. But two, so among those that are affected, some are affected more severely than others. So some people would have only the ECG abnormality, whereas other people, for instance, would have the ECG abnormality and arrhythmic events. And you could also have individuals, indeed, who don't even manifest any disease manifestations. This is one of the outstanding challenges. The other outstanding challenge is the fact that, despite extensive genetic testing of the known genes in some probands and some families, they remain genetically lucid, in that we don't find a likely genetic defect in a minority of families. And of course, that hinders genetic testing and implementation of genetic testing in such families. Dr Greg Hundley: What was the question you were going to answer with your study? And tell us a little bit about your study design and your study population. Prof Connie Bezzina: Yeah, so essentially, we figured that assigning these disorders to one large genetic defect might be an oversimplification of biological phenomenon. So we hypothesized that even in these Mendelian disorders, the inheritance of additional genetic factors alongside the familial mutation could contribute to risk. Of course, there will be other factors such as environmental factors, which we did not tackle in the study. The central hypothesis of the study was that common genetic variation, which is present in the germ population, could modulate the effect of the familial genetic defect of the Mendelian mutation. So in order to do this, we assembled a large consortium of investigators from multiple centers in Europe, in North America and Japan, worldwide, to bring together about 1700 probands with the long QT syndrome. So we tested this hypothesis in the long QT syndrome because we figured, among the rare inherited rhythm disorders, it's one of the more common disorders. Also, because each individual center has too few patients. To do this locally, we put this group of investigators together to come up with 1700 probands. The study design was a genome-wide association study with a case-control design, where we tested the association of millions of SNPs littered across the genome with susceptibility for the disorder. So this led us to identify three single-nucleotide polymorphisms that are associated with susceptibility for the long QT syndrome. What we immediately saw is that, actually, these three SNPs, perhaps not surprisingly at all, had been previously associated with the extent of the QT interval, with QT interval in the general population. This is not surprising, of course, because repolarization is a central part of physiological mechanism in the long QT syndrome. So this basically indicated overlap between genetic control of the QT interval in the germ population and susceptibility to the long QT syndrome. So the fact that the three SNPs that we identified as long QT syndrome susceptibility SNPs had been associated with QT interval duration in the germ population, we felt that that was pointing to assure genetic underpinnings between these two phenotypes. So we went on to investigate that by looking at the correlation between the odds ratio for long QT syndrome susceptibility and the effect that these SNPs have on QT interval in the germ population. And in fact, we found a very high correlation between those. So essentially, this pointed to sure genetic factors between QT interval in the germ population and long QT syndrome susceptibility. Of course, we wanted to look for disease variability. The next thing we wanted to do was whether these SNPs could actually explain disease variability. Now, this was perhaps the most disappointing part of the study, because when we constructed a polygenic risk score based on SNPs that impact on the QT in the germ population, we found no relation to QT interval among patients, and also no relation to life-threatening arrhythmic events among the patients. We think that this is because our patients... or probrands. They're primarily probands, so they are all more sick. So we didn't have enough variability in our patient set to identify an association with disease variability. And in fact, this is at variance with previous studies that tested individual SNPs, and even our own studies with smaller polygenic risk scores that did find an association between a polygenic risk score based on QT SNPs and QT prolongation and events among patients. So we think that this is certainly something to study further in the future, in larger patient sets where we not only have the probands, but also their relatives, their mutation-carrying relatives, which will give us a bigger variability to actually test this hypothesis. So we think that looking at probands actually was a very good design to find susceptibility variance but was not maybe a good design to find SNPs or polygenic risk scores to test their effect on disease variability. Dr Greg Hundley: It sounds like you've found certain gene low PSI that indicate a predilection for prolongation of the QT interval, but not necessarily are those gene low PSI consistent with who's going to experience an adverse cardiovascular event as a result of their genetic constitution. Is that a fair statement? Prof Connie Bezzina: Well, I think that the setting, because we had probands, they were the most sick people in their families. I think to have stronger conclusions on that, we need to test the polygenic risk scores in families where there are people who are differentially affected. Dr Greg Hundley: I see. I- Prof Connie Bezzina: We had too-narrow of a variability in a probands-only design, as opposed to a study where we would have probands who are severely affected and mutation-carrying relatives who are less severely affected. Dr Greg Hundley: Very nice. So that puts that clearly into context. This was a massive effort. You have quite a list of investigators, and you mentioned you had to gather so many sites. How would you conduct that next study? Would you need another large collection of individuals and many sites to take that on? Prof Connie Bezzina: Yes. I'm a geneticist, and geneticists always want larger, larger numbers, and I'm also one of those. So I'm interested in explaining as much as possible into individual variability. And I think to do that properly, I think we should go preferably for a similar design where we will approach the same centers. And hopefully, we can organize the next study, which will have these probands and their relatives. Dr Greg Hundley: Now, just quickly, for us working in the clinic, how should we approach genetic testing in patients with long QT? Prof Connie Bezzina: At the moment, I think our findings don't have an immediate impact. I think our findings tell us about the genetic architecture of the disorder. And actually, one thing I haven't gone into yet is the fact that what we also found is that patients who do not have mutations in the no-long QT genes, which were called mutation-negative, which are about 20% of all long QT syndrome probands, actually have a higher burden of these common variants that prolong the QT interval. So we think, actually, that mutation-negative long QT syndrome probands will not have a Mendelian large effect variant but will have perhaps a higher burden of these QT-prolonging alleles. Therefore, I think this has direct implications for clinical genetics of these patients, because if you have a proband in whom you don't find a mutation in the known genes, you could think that maybe it is not monogenic, which has implications because you don't have a single genetic defect to test on that family. One would need to keep follow-up of more family members until we understand more about the genetics of those individuals. Dr Greg Hundley: So Connie, this has been just a wonderful discussion. Any additional studies examining the genetic architecture of individuals that we need to think about for the future? Prof Connie Bezzina: Sure. So for long QT syndrome in particular, as additional SNPs that modulate the QT interval in the germ population are identified, it will be very important to incorporate these into larger polygenic risk scores, and see whether we could have a better discriminative capacity of such polygenic risk scores in discriminating between severely affected and less severely affected people, or who is more at risk for an arrhythmic event. Outside of long QT syndrome, I think there's a lot of work to be done with respect to the likely complex inheritance of many of these disorders that we previously considered to be Mendelian. So for instance, ongoing work in our group concerns Brugada syndrome, where we're seeing the same kind of thing, and hypertrophic cardiomyopathy, where we're seeing the same kind of inheritance. Dr Greg Hundley: Well listeners, on behalf of both Carolyn and myself, we look forward to catching you on the run next week. Take care. This program is copyright the American Heart Association 2020.

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, Director of the Poly Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Today's feature discussion is the first huge look at the global, regional and national burden of calcific aortic valve disease and degenerative mitral valve disease over a huge period, from 1990 to 2017. Very important discussion coming right up after this coffee chat. Greg, do you mind if I go first? Dr Greg Hundley: Go ahead, Carolyn. Dr Carolyn Lam: The first paper I want to talk about applies novel single cell transcriptomics to unveil new insights into pressure overload cardiac hypertrophy. Here's your quiz, Greg, ready? Dr Greg Hundley: Well, I'm choking on my coffee here, but go ahead. Dr Carolyn Lam: All right, I was thinking of asking you about single cell transcriptomics but let me just tell you the results. Single cell RNA sequencing is a new and rapidly advancing technique that can comprehensively characterize gene expression and relationships among individual cells. Dr Wang from Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, and Peking Union Medical College and colleagues analyze the transcriptomes of 11,492 single cells and identified major cell types, including both cardiomyocytes and non-cardiomyocytes based on their molecular signatures. They did this at different stages during the progression of pressure overload induced cardiac hypertrophy in a mouse model. Their findings not only illustrated dynamically changing cell type crosstalk doing pathological cardiac hypertrophy, but also shed light on strategies for cell type and stage specific interventions in cardiac disease. For example, subtype switching of macrophages was found to be a key event underlying the transition from normal to decline dejection fraction in cardiac hypertrophy. Thus, targeting macrophages in hypertrophy for example, during the switch could attenuate disease progression. All of this is discussed in an editorial by doctors, Zhang and Zhou from University of Alabama in Birmingham. Dr Greg Hundley: Oh wow. Carolyn very important macrophage infiltration and another role for those, that cell type. Well, my first paper gets at the topic of reversal of these factor Xa inhibitors. In this particular patient population, it's the situation where we're dealing with intracranial hemorrhage. The article comes from Dr G Morgan Jones and colleagues from the University of Tennessee Health Sciences Center. Since the approval of oral factor Xa inhibitors, there have been few papers published really regarding the ability to neutralize the anti-coagulate effects of these agents, particularly after intercranial hemorrhage. Dr Carolyn, this is a multi-center, retrospective, observational cohort study of 433 patients. Then it received apixaban, or rivaroxaban, and then developed an intercranial hemorrhage. They then subsequently received prothrombin complex concentrates in that period of time between 2015 and 2019. Dr Carolyn Lam: Wow. How did these participants who had intracranial hemorrhage, how did they fare after receiving these prothrombin concentrates? Dr Greg Hundley: Yeah, well, administration of the prothrombin complex concentrates after, apixaban or rivaroxaban in the setting of intracranial hemorrhage, provided a high rate of excellent or good hemostasis. That was in nearly 82%, coupled with an adverse consequence of 3.8% of those experiencing a thrombosis. Thrombosis occurred in 25 patients who had a total of 26 thrombotic events of which 22 occurred in the first 14 days, following the prothrombin complex concentrate administration. One patient had documentation of an infusion related reaction. For the full cohort of patients, in the hospital mortality was 19% and the median ICU care and hospital length of stay were two and six days respectively. Carolyn, these cohort analyses seemed to demonstrate the possibility of success and similar to other observational cohort studies. The results of this study suggest that future randomized control trials evaluating the clinical efficacy of these prothrombin complex concentrates in patients with factor Xa inhibitor related intercranial hemorrhage are needed. Dr Carolyn Lam: Nice, Greg. You know what? I'm going to start with a quiz. True or false, heart failure with reduced ejection fraction is characterized by blunting of the positive relationship between heart rate and left ventricular contractility known as the force frequency relationship? Dr Greg Hundley: Well, Carolyn, this is one of those where if I go 50/50, you'll knock out the wrong answer. Let's say, I'm going to go, true. Dr Carolyn Lam: You're so right, Greg. This next paper really deals with this. It's from corresponding author, Dr Witt from Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds in UK and colleagues who previously described that, tailoring the rate responsive programming of cardiac implantable electronic devices in patients with HFrEF based upon individuals noninvasive force frequency relationship data, really improves exercise capacity. Addressing this reduce force frequency relationship and HFrEF.  Now in the current paper, they sought to examine whether using force frequency relationship data to tailor heart rate response in HFrEF with inpatients, with HFrEF and cardiac implantable electronic devices would favorably influence exercise capacity and left ventricular function six months later. They conducted a single center, double blind, randomized parallel group trial in 83 patients with HFrEF. With a cardiac implantable electronic device and randomized to tailored rate response programming based on these individuals force frequency relationship versus conventional age guided rate response programming. The primary outcome measure was changed in walk time on a treadmill walk test. Dr Greg Hundley: Wow, Carolyn. So this is a really detailed analysis. What did they find? Dr Carolyn Lam: They found that rate adaptive cardiac implantable electronic device programming taking into account the at normal force frequency relationship in these patients, was associated with improved exercise time. Force frequency relationship guided heart rate settings had no adverse effects on left ventricular structure and function. While conventional settings were associated with a reduction in left ventricular ejection fraction. Out of the box age guided rate adaptive pacing, might be a sub optimal choice in patients with heart failure and an assessment of the force frequency relationship might be of clinical benefit in facilitating personalized rate adaptive programming. Dr Greg Hundley: Very nice. Dr Carolyn Lam: Thanks Greg, but there's other stuff I want to tell you about in this issue. There's a research letter by Dr Gambier on Molecular Imaging of Infective Endocarditis with Floral Multiple Trials PET-CT. This is the first time that a Florine 18 PET tracer has been used to specifically image bacterial infection of the heart valves with high sensitivity and specificity in an animal model. Dr Greg Hundley: Oh, good job, Carolyn. Those flooring tracers, very interesting. Another application perhaps. Well, in a perspective piece, I have an article Carolyn from Dr Orly Vardeny from University of Minnesota Medical School in Minneapolis and remembers the prior cardiovascular complications from influenza. And how those experiences may be useful in anticipating some of the cardiovascular complications that we may see from SARS-CoV-2. In a separate article, Dr Aatish Garg and collaborators from VCU Health, present an ECG case of syncope in an individual with severe aortic stenosis status post bioprosthetic aortic valve replacement and coronary artery bypass grassing. Who also has paroxysmal AV block? Then finally, Carolyn, Professor Concepcion Peiró from Universidad Autónoma in Madrid. Has an on my mind pace discusses ACE inhibition and our abuse in relation to the SARS-CoV-2 to virus bonding to ACE two binding sites within the respiratory epithelium. Well, Carolyn, how about we get on to that feature discussion? I can't wait to hear about aortic and mitral valve disease over nearly 30 years. Dr Carolyn Lam: Let's go Greg. Nondramatic valvular heart disease is really common throughout the world. However, no studies have previously estimated their global or national burden, that is until today's feature paper. That's part of the Global Burden of Disease, or GBD, 2017 study. I am so pleased to have with us a corresponding author, Dr Greg Roth from University of Washington. As well as Victoria Delgado, our associate editor from Leighton University Medical Center. What a great topic to discuss. Nondramatic valvular heart disease, meaning calcific aortic valve disease, degenerative module valve disease, all the stuff we see and have to deal with now. Greg, could you please tell us about this GBD effort and really what you found? Dr Greg Roth: Let me tell you a little bit about the Global Burden of Disease Study and then why we wanted to explore this question and then what we found. I am the lead for cardiovascular research at the Institute for Health Metrics and Evaluation in Seattle at the University of Washington. We're the coordinating center for the Global Burden of Disease Study. It's now in its second decade, and it's a large-scale effort to quantify the lost health due to early death and disability for every country in the world. This is a huge effort with over 5,000 people around the world working on it. We work closely with governments around the world, as well as the World Health Organization, as well as county, state, and other authorities in the US. Our goal is really to bring together all of the evidence in the world to bear on important health policy questions. One of the areas that I've had a long interest in is valve disease. I'm a practicing cardiologist at our county hospital here in Seattle, as well as an echocardiographer. I was really excited by the idea of bringing together my passion for taking care of patients with valve disease and looking at how to use diagnostic imaging to take better care of them and the disease modeling research that I do at the institute. We decided a couple of years ago after exploring the global patterns of rheumatic heart disease, that we would turn our focus towards these really important questions of non-rheumatic valve disease. There's obviously a very large literature and lots of active research around the clinical pathways that we need to follow for patients with calcific valve disease and mitral valve disease that's not due to rheumatic causes. Obviously in recent years, we've got amazing technologies and interventions that we're using more and more frequently like percutaneous interventions. However, we had not done the work to turn this really interesting tool, the Global Burden of Disease Study, towards looking at these important causes. We pulled together every data source we could find on the population level burden of nonrheumatic valve disease and then using a range of techniques, and we rely heavily on tools that come out of data science. These include computer disease modeling tools that we've developed as well as ensemble models and other sort of big data approaches to pull all of this together into comparable, consistent estimates of death and prevalence. Then we're also really interested in using those to estimate what we call summary metrics of health, like disability adjusted life years. We do this for a very long time series. So we went back all the way to 1990 and we looked all the way to 2017. Then we're able to get a really good sense of not only what the impact of these diseases are, but how they compare to the 350 other diseases that we estimated in exactly the same way for the Global Burden of Disease Study. Also, where is the burden of these particular conditions going up? Where is it going down? We're really excited to be able to pull that together into this paper. In which we report the global, regional, and national burdens of calcific aortic valve disease and degenerative mitral valve disease. As well as a right sided valve disease that's not due to congenital endocarditis causes, which we estimate separately in the study. Dr Carolyn Lam: Greg, you say, you're excited. I can definitely speak, I think on behalf of both Victoria and Augie, that we're the ones excited publishing this really great piece of work here in circulation. You know personally, I'm a great fan of your work in GBD. Tell us the results. Dr Greg Roth:  What we found was that in 2017, there was an estimated 12.6 million cases of calcific aortic valve disease in the world and 18.1 million cases of degenerative valve disease globally. With higher rates of calcific valve disease, among men and higher rates of degenerative valve disease among women. Now that is an aggregate. We've produced estimates for every country in the world and for larger countries with more than 200 million people, we've gone down to what we call the first administrative level. So, US states, Chinese provinces, and we do this in the larger countries, but when you add it all up, you get those numbers. We also found that there were just over a hundred thousand deaths globally each year due to calcific aortic valve disease and about 35,000 deaths reported due to degenerative mitral valve disease. I think this is really interesting because of course, as clinicians, we have a lot of experience with sources like cohort studies, and trials, and registries, but we have not actually looked at what's actually the world's largest public health reporting system, which is vital registration, meaning death certificates. Now, most of us have filled out that certificates and we always wonder, how reliable are there? And there's clearly limitations. In fact, a huge amount of our work at the Global Burden of Disease Study is dealing with the limitations of death certificates, looking for bias, and adjusting that bias when we can, but these are death certificates where somebody's entered these causes as the underlying cause of death. I think when that actually shows up on a death certificate, that's actually a real signal to us that there was a physician out there who felt pretty strongly that that was the sort of trigger that led to the patient's death. We also found that aging and population growth are leading to about a hundred percent increase over this period of time over the last 25 years in the number of deaths due to these nonrheumatic valve diseases. If we age standardized, we see that the trend is flat, but if you're running a health system or a minister of health, you need to hear that message that with aging and population growth affecting almost every country in the world, you're going to see dramatic rises in the number of cases of both of these conditions showing up on the doorstep of all of your hospitals. Dr Carolyn Lam: Fantastic Victoria, could you put these findings in context for us and maybe take us behind the scenes a little bit at what the editors thought? Dr Victoria Delgado: These are very important data, because so far, for example, we have, as Greg said, registries and one of the most known registries was for example, in Europe, The Valvular Heart Survey that was done in 2001, if I remember well. Has been redone recently, it was last year published in circulation. The other one with a very large data is coming from counties. With similar data to the results that are publishing now. For example, if you compare those two registries with much smaller populations, in US, they always report much, much frequently the genetic mitral valve regurgitation. While in Europe, aortic stenosis is the most frequent one, calcific aortic stenosis. Here, I was again surprised with in the global population that again, degenerative mitral valve regurgitation is much more prevalent than calcific aortic stenosis, but you can see that there was an increase of 124% in the prevalence of calcific aortic valve disease in 2017. I wonder if this is related to the awareness of the risk associated with aortic stenosis and they invent of a new therapies, transcatheter therapies, with the TAVI for example, or transcatheter aortic valve replacement, which has opened the door for an effective treatment for many patients that before were simply denied for surgery. I don't know if you have further insights into that. Dr Greg Roth: Yes. I think that's a really important point, that we see a lot of variation in the data. While we have millions of death certificates to look at all around the world. Really scores of millions, where we can look for trends and patterns. The population level data on nonrheumatic valve disease is actually quite limited compared to most diseases. We did a very aggressive perspective review of the published and gray literature and found about 50 sources reporting prevalence for these conditions that were usable in our study. For the most part, those studies are not long time series. We have to estimate trends, piecing together data from different populations. Now, there are a couple of places in the world where you can get a long trend of time where they've gone back repeatedly in the same population and looked with echo, which you obviously need here to make these diagnoses. As far as we can tell, and these are just a handful of studies, the trend is flat. We don't see large increases. Now, the increases in our study were completely driven by aging and population growth and the age standardized rates. The epidemiologic pattern for this disease is that it's flat and for mitral valve disease, maybe trending down a little bit. I think it's clear that in places where there's been a lot of attention paid either because of new therapies, like TAVR or new access to diagnostic screening with the growth of echo cardiography and other screening methods, that is a limitation of the study, for sure. I think what it really focuses me on is the idea that we need better data. We need to think about ways and probably more cost effective ways of surveilling for these conditions, but I'll tell you something that was really interesting, that we found is that, in the United States where we relied heavily on administratively coded data, because we have that in a uniform format for every state and we have a long time series for that, and we have complete vital registration. We looked at the state level and we found that the all ages rate, was actually going up. Meaning it wasn't just population growth and aging, but in about a third of the states, the true epidemiologic rate of the disease was going up. Meaning it's becoming more common even if you control for the change in age structure of a country like the United States over time. I think that given the fact that we're seeing this explosion of obesity around the world, and we know that atherosclerotic risk factors can be a major driver of let's say calcific aortic valve disease. I mean, an interesting question is, is valve disease going to be sort of a canary in the coal mine? Are we going to see more of it at younger ages? Traditionally it's been the oldest patients who actually survived the longest and tend to be healthier, who we can actually find having the disease, but I wonder, are we going to see more of that as patients present with more obesity. Unfortunately we know that reversing or controlling those atherosclerotic risk factors hasn't paid off in big ways for preventing calcific aortic valve disease. It's complex and like mitral valve disease, clearly there's likely to be a very strong genetic component as well. Dr Carolyn Lam: Greg, you mentioned a little bit more about the age effect, but you did mention some sex differences. Could you just clarify a little bit about that and maybe the interaction between the two? Dr Greg Roth: What we've all been taught, or at least what I was always taught, was that there was more mitral valve disease in women. We actually did find that in the study and that was reassuring because when we went back to look for the source of that sort of common teaching, actually, it's pretty hard to find. I think it actually comes, my guess is, from a lot of people's clinical practice. To see that match-up between what we thought was going to be true in terms of the relative prevalence by sex for these two major diseases, calcific aortic valve disease and degenerative mitral valve disease was reassuring. It suggested that the data we have is actually picking up on real patterns and patterns that match sort of our clinical experience as well. One of the interesting things about the interaction between age and sex, is that women live much longer on average than men. As women age into those oldest years, what we actually see is a decline in the burden of disease. There's an increase in stroke, but for everything else, those women are truly survivors. Actually we see less bowel disease and cardiovascular disease in general, in the oldest old women. What we do see is a massive rise in cognitive impairment and dementia. That's a very active area of research for us right now. The interaction between atherosclerotic risks, which can drive things like valve disease and of course, coronary disease and stroke and then the cognitive impact is a really important area of research. There are a couple of great papers that have come out even just in the last few weeks. I think this question of how risk is going to impact people in those oldest age groups? Is really important. We know the population is aging. We know that in some places, life expectancy is increasing to the point where we really need to rethink what the disease patterns are going to be in the oldest old. Dr Carolyn Lam: Indeed. So the feminization of aging is kind of what I like to call it, but yikes Victoria. Could I maybe ask you to please give the final words of advice and maybe the take home messages? Dr Victoria Delgado: I think that this data are really welcomed because as Greg said, we need to understand better how we can modify the prognosis of these prevalent and how we can tackle it and for that we need data. I think that these are very welcomed data. Now, how we are going to do it in the future? That's a great question. I don't have the answer right now, but I think that increasing the awareness that nonrheumatic valvular heart disease can impact as well on the outcomes of the population, is important to know. I think that people need to have access to diagnostics best particularly echo cardiography is very available imaging technique and very feasible. We can have right now developments where we can do the echo cardiography with our phone by adding one of the probes. I think that in the future, we may see more and more valvular heart disease that probably was already there, but we just need to increase the awareness. From those data, learn how we can treat those individuals if they need and how we can improve the outcome of these individuals. Dr Carolyn Lam: Thank you, Victoria. Thank you, Greg. More awareness and more good data needed. Thank you, audience, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week. Dr Greg Hundley: This program is copyright the American Heart Association, 2020.  

  This month on Episode 111 of the Discover CircRes podcast, host Cindy St. Hilaire highlights three featured articles from the March 27 issue of Circulation Research and talks with Dr. Matthias Nahrendorf  and Dr. Maximilian Schloss about their article Modifiable Cardiovascular Risk, Hematopoiesis and Innate Immunity.   Article highlights:   Liu et al. Genetics of Transposition of the Great Arteries   Park et al. Mild Lipid Abnormalities and ASCVD in the Young Yan, et al. Gut Flora Adjusts Blood Pressure By Corticosterone Transcript Cindy St. Hilaire:              Hello and welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh. Today, I'm going to share with you articles selected from the March 27th issue of Circulation Research, as well as give you a hint of the cutting-edge ideas in the Compendium on atherosclerosis. We'll also have a discussion with Dr Maximilian Schloss and Matthias Nahrendorf about their article On Modifiable Cardiovascular Risk, Hematopoiesis And Innate Immunity. So, first the highlights.                                            The first article I'm sharing with you is titled Exome-Based Case Control Analysis Highlights the Pathogenic Role of Ciliary genes and Transposition of the Great Arteries Exome-Based Case-Control Analysis Highlights the Pathogenic Role of Ciliary Genes in Transposition of the Great Arteries. The first authors are Xuanyu Liu and Wen Chen and the corresponding author is Zhou Zhou from Peking Union Medical College in Beijing, China. In normal healthy hearts, the aorta develops from the left ventricle and the pulmonary arteries from the right ventricle, but in the common congenital heart malformation called transposition of the great arteries or TGA, the plumbing of these two major vessels is switched. Thus, the pulmonary arteries arise from the left ventricle and the aorta from the right.                                            This is a life-threatening condition, requires surgery in the earliest days of life and currently, the genetic etiology of this congenital disease is largely unknown. To identify the genetic drivers of transposition of the great arteries, the authors of this study performed whole exome sequencing of 249 TGA patients and, in 66 cases, they were actually able to do exome sequencing on their parents as well. The analysis identified 82 candidate genes in which the allele variant or mutation that was found in TGA patients was predicted to alter protein function.                                            Interestingly, a quarter of these mutations or variants were found to be in genes that are involved in cilia function. So, the cilium is an organelle that's found on all eukaryotic cells and is in the shape of a slender protuberance that projects from the much larger cell body. Recently, cilia have been identified as playing a central role in the pathogenesis of congenital heart diseases, and it has been suggested that congenital heart disease may be a new class of ciliopathy. Transposition of the great arteries has been hypothesized to arise from disturbances in the left right patterning during embryo development, and cilia are required cellular organelles and they are essential for left-right axis determination in early development. These findings add to the growing body of evidence that has identified a role of cilia genes and congenital heart disease and may lead to future prenatal diagnostic screenings.                                            The next article I want to highlight is titled Mildly Abnormal Lipid Levels, but Not High Lipid Variability, Are Associated with Increased Risk of Myocardial Infarction and Stroke in ‘Statin-Naive’ Young Population: A Nationwide Cohort Study. The first author is Jun-Bean Park and the corresponding author is Hyung-Kwan Kim from Seoul National University Hospital in Seoul in the Republic of Korea. High levels of lipids in the blood increase a person's risk of cardiovascular disease, and evidence suggests that this risk builds over lifetime. However, in young adults, and in this case, young adult means any individual between 20 and 39 years of age. In young adults, relatively little evidence is available that identifies individuals at high risk for atherosclerotic cardiovascular diseases, except for very high LDLC levels.                                            Variability in lipid levels has recently emerged as a predictor of adverse clinical outcomes and lipid level variability may be causally linked with the atherosclerotic cardiovascular disease risk. This is because theoretically, high lipid levels can induce fluctuations in the atherosclerotic plaque composition. These fluctuations result in plaque instability and rupture and ultimately, plaque related clinical events, such as myocardial infarction. However, high lipid level variability may merely reflect other risk factors or confounders for atherosclerotic cardiovascular diseases, including unhealthy lifestyle and unrecognized comorbidities. This study therefore examined health data of close to two million Korean individuals aged 20 to 39. None of them had ever been treated for high cholesterol with statins nor had any of them suffered any myocardial infarctions or stroke.                                            Over a four-year period, the subjects had undergone at least three lipid measurements as part of their general health assessments and then they were followed for a further four years or until death. The data showed that high baseline lipid levels was linked with an increased risk of adverse cardiovascular events, and in particular, myocardial infarctions. They also found that individuals who exhibited high lipid variability, so sometimes getting high readings, sometimes getting low readings, these individuals who exhibited high variability and lipid level measurements were not at any greater risk of such cardiovascular events. While such up and downs have previously been linked to cardiovascular disease, this study argues that perhaps statin use in other cohorts may have contributed to the variability and thus confounded research interpretation, an issue that was specifically avoided in this study. Together the results indicate that lipid in young adults can indeed indicate future cardiovascular risk and therefore suggest lipid-lowering strategies could be beneficial for this age group.                                            The next article I want to share with you is titled Intestinal Flora Modulates Blood Pressure by Regulating the Synthesis of Intestinal-Derived Corticosterone in High Salt-Induced Hypertension. The first author is Xuefang Yan and the corresponding authors are Zhe Wang and Qunye Zhang from Shandong University in China. Hypertension is highly prevalent in the adult population all over the world and it is a major risk factor for heart disease and stroke. A high salt diet can help to drive hypertension pathogenesis, but complete details about the mechanisms by which high salt intake shapes vascular pathology are lacking.                                            Recent studies show that fecal transfer from salt hypertensive to salt normotensive animals can lead to hypertension in the recipients, and this suggests that perhaps gut flora may play a role in hypertension. In the article by Yan and colleagues, they show that rats on a high salt diet have altered gut flora profiles and in particular that levels of the bacterium, Bacteroides fragilis, was reduced. Analysis of intestinal metabolites and substrates in high salt diet fed rats also showed that levels of arachidonic acid, which is produced by this bacterium, were low and levels of the stress hormone, corticosterone, which regulates blood pressure, were elevated.                                            The team went on to show that supernatants from this bacterial culture could prevent corticosterone production in the intestinal tissue of high salt fed mice as could direct treatment with arachidonic acid. Moreover, both B. fragilis and arachidonic acid were found to be lower in the feces of humans with hypertension compared to that of healthy controls. The results suggest B. fragilis and arachidonic acid normally curb corticosterone production and could therefore be novel targets for hypertension treatment strategies.                                            The last thing I want to mention before we switch to our interview is the Circulation Research Compendium on Atherosclerosis. The last compendium on this topic was back in 2016 and this new compendium provides the most cutting-edge ideas in the field. The topics highlighted in this compendium are polygenic scores to assess atherosclerotic risk, clinical perspectives, and basic implications, epigenetic reader proteins and cardiovascular transcriptional programs, sex as a biological variable in atherosclerosis, neutrophil extracellular traps in cardiovascular diseases, CD31 as a therapeutic target in athero, interleukin-1 and the inflammasome as therapeutic targets in cardiovascular disease, non-coding RNAs in vascular diseases, intracellular aspects of macrophage immunometabolism in atherosclerosis, single cell RNA sequencing in atherosclerosis, vaccination strategies and immune modulation in atherosclerosis and we have an update from the group leading the One Brave Idea. Please check out this compendium.                                            All right. So, now we're going to switch over to our interview portion of the podcast. I have with me today Dr. Matthias Nahrendorf, who is a professor at the Center of Systems Biology at Massachusetts General Hospital Research Institute and Harvard Medical School and his research fellow, Dr. Maximilian Schloss. Today, we're going to be discussing the article Modifiable Cardiovascular Risk, Hematopoiesis, Innate Immunity, which is part of our Compendium on Atherosclerosis. Circulation Research puts together two to three compendiums annually and this current one is the Compendium on Atherosclerosis. We will have two additional compendiums planned for 2020. One on Obesity, Metabolic Syndrome and Cardiovascular Disease and that should come out in late May and another on Atrial Fibrillation scheduled for June. So stay tuned.                                            So, thank you very much for being with me here today, Matthias and Maximilian. Matthias Nahrendorf:    Thanks for having us. Maximilian Schloss:        Thanks for having us. Cindy St. Hilaire:              So, I really enjoyed this review article. I actually learned a lot. I also really liked your cartoons at the end, so maybe we can talk about those a little bit later, but what it's on is essentially the role of inflammation and cardiovascular disease and years of study, which have recently culminated in the completion of the CANTOS trial, have showed us that reducing inflammation can help reduce cardiovascular events. When we look at the factors that we know drive cardiovascular disease, it's things like bad diet choices, lack of exercise, stress, and inadequate or disrupted sleep and in this article you make the more nuanced argument that these modifiable factors are in fact influenced by the innate immunity. So, before we dig too deep into what you are really discussing in this article, could you maybe give us a brief introduction to the role of innate immunity and cardiovascular disease initiation and progression? Matthias Nahrendorf:    Sure. Yeah. So, I think one very instructive experiment that had been done by more than one lab actually almost two decades ago, is stopping innate immune cells from migrating to atherosclerotic plaque by deleting the chemokine MCP-1 or the chemokine receptor CCR2 in mice that have a propensity to develop atherosclerosis. What became apparent is that these mice, despite having very high blood cholesterol levels, they don't really develop atherosclerosis. This really led the whole field now almost 20 years ago, to the insight that it's not only the hypercholesterolemia, it's also the immune system that contributes to the disease. So, innate immune cells, most numerous neutrophils and monocytes then in tissue also macrophages and they're meant to defend us against infections and they support healing. In this particular setting, they are probably doing more harm than good because they promote inflammation in areas where inflammation shouldn't be i.e., in the vessel wall. Maximilian Schloss:        Yeah, I would add that what Matthias said is that basically it's all about a balance between necessary inflammation and too much inflammation. If we take, for instance, myocardial infarction as an example, we need a certain amount of inflammation, local inflammation. We need a recruitment of innate immune cells like neutrophils and monocytes and eventually macrophages, to do their job. For instance, phagocytizing a dying cardiomyocytes or inducing fibrosis. So in this example, we need inflammation, but what we see in different models where we can manipulate inflammation being at reducing or increasing inflammation, we can see that if we do either/or then wound healing and scar formation is impaired. I think that's all we are interested in studying not only the mechanisms, how inflammation can be increased or decreased, but also what is actually the perfect balance in view also of finding ways of improving outcomes in cardiovascular patients. Cindy St. Hilaire:              One of the things in my research, so I focus on cardiovascular calcification, which is very hard to do in a mouse. They don't like to calcify similarly like they don't like to make plaque without a proper genetic background. Are there aspects of the mouse versus the human innate immune system that are very different? I mean I know specific receptors are slightly different, but in general, are they matched up pretty well or is there things that are quite different about them? Matthias Nahrendorf:    I think the answer is both and there are very important parallels and then there are very important differences. So, one important difference is just if you look at sheer numbers and the contribution of immune cells in the blood and, possibly also in the plaque, can be quite different. So, recent studies that use unbiased profiling in human plaques, for instance, say that there's quite a lot of lymphocytes and we still have to understand whether this is due to the retrieval or if it says species difference or the situation, but I think there are important differences. On the other hand, I think that it really make sense to study mice because a lot of the important discoveries about the immune system in the setting have translated to humans. Cindy St. Hilaire:              Like the IL-1 beta story. Matthias Nahrendorf:    That's right. Yeah. Cindy St. Hilaire:              So, actually one of the topics that you started out with in your article is on the role of hematopoiesis in cardiovascular disease. You had a beautiful paper years ago actually with my colleague at University of Pittsburgh, Partha Dutta, who's right down the hall from me, where you guys showed that myocardial infarction itself further exacerbates atherosclerotic plaques mid part through recruiting monocytes from the spleen and mobilizing the immune system. So, I'm wondering, what are the role of the cells when they get mobilized? You talk about these modifiable risk factors of stress and sleep interruption, unhealthy diet. So, how can these risk factors help or promote this mobilization of hematopoietic cells? Matthias Nahrendorf:    Yeah. So, I think that early on when we thought about going down this road and studying these risk factors, even before going there, you realize that the cells that we're interested in, innate immune cells are very short lived. So they live on the order of hours or days. So, they're really produced just in time. That's different to lymphocytes and resident macrophages, which have much longer lifespans. So, this really triggered the insight that we should look at production and release because it's a just in time supply situation. So, what we were wondering is whether in the setting of cardiovascular disease, whether production rates are increased and we now know and a number of labs have studied hematopoiesis in this setting including Fil Swirski, Alan Tall, and some others.                                            We now know that this is really the case, so hematopoiesis increases in chronic atherosclerosis. It increases in acute myocardial infarction and increases in heart failure. What we don't know is what mechanisms actually ramp up blood cell production and we're beginning to understand that the sympathetic nervous system is involved. But I think we only see the tip of the iceberg here. That's why we wanted to study modifiable risk factors, because if you look at others such as high cholesterol, once the insight was gained that lowering cholesterol is helpful, we had the statins which make a huge change. So, we hope to repeat that. Cindy St. Hilaire:              Maximilian, one of the things that you brought up is this balance. The inflammation's a little bit good and then it's a little bit bad or a lot bad. So, where is that good and bad spectrum in terms of mobilizing hematopoiesis or hematopoietic cells? Maximilian Schloss:        Yeah. I think that depends a bit on the disease type or we're talking about a chronic disease or an acute disease? For instance, to stay at the example of myocardial infarction, once cardiomyocytes become ischemic, they will release certain chemokines and cytokines into the blood, which then circulate to the bone marrow and tell the cells that leukocytes need to leave the bone marrow to enter the blood circulation system and then go to the heart to fulfill their very important functions there. Once the cells leave the bone marrow, the bone marrow need to reproduce themselves, then this process starts of hematopoiesis and there we can go back again to the concept of a balance. Of course, there is a certain beneficial physiological need of cell production, but one sees mechanisms so to say maybe go out of control and too many leukocytes are produced and released to the blood.                                            Then that again impairs patient outcome. There are very many papers, clinical papers, who have shown that leukocyte counts after myocardial infarction have a certain U shape relationship with the outcome. That I think is best described that if leukocyte counts are very high, that they actually negatively correlate with the outcome of MI patients. If you look at the bone marrow specifically, there are certain mechanisms, which we know, and what we are more closely looking at now, what are actually the modifier of this process, what are the signals which tell these cells to secrete more hematopoietic factors or quiescence factors? I think that's what also the Review is a little bit about. Cindy St. Hilaire:              Yeah, it's great. So, you were speaking about that kind of U-shaped curve in the release of these cells. Do we know based on some of the other things you spoke about, I guess I'm thinking about like diet or exercise or sleep in contributing to that release after an event like myocardial infarction. Is that known yet or has anyone looked into that? Matthias Nahrendorf:    Yeah. So, I think we're in the very beginning of understanding what's happening acutely. There's more knowledge on the chronic side and this is what we've been working on. Often the things that influenced the chronic situation can be quite different from what happens acutely. So I think in general, we're just beginning to understand what happens in acute myocardial infarction. Well, we know for instance is that exercise doesn't compromise the release and supply of leukocytes that's necessary in acute infection or acute myocardial infarction. So, if the mouse or the individual was exercising before the event, that may reduce overall leukocyte levels, but not to a degree that it's harmful. Cindy St. Hilaire:              Yeah. You can't exercise your way beyond a certain point. Matthias Nahrendorf:    Maybe that's also possible. If you run more than one marathon a day, I'm sure that's… Cindy St. Hilaire:              That will do something else. Matthias Nahrendorf:    Yeah. Cindy St. Hilaire:              Actually, so one of the interesting things that I saw in the article was when you were talking about diet and the role of diet in innate immunity, which is something I really never thought about, and you did bring up things like intermittent fasting. Can you discuss what's known at least scientifically about how that kind of diet timing can impact the immune system and therefore maybe cardiovascular disease? Matthias Nahrendorf:    So, that's a very emerging field. There's very little known about this. I think it's very interesting because very relevant and a lot of people are excited about it, but it's basically, from what I know, it's mostly two papers that were published, I think both in Cell, and they say that intermittent fasting leads to a decline of cells that are in circulation. So, that's a very exciting observation. I think it's similar insight as to discovering that immune cell levels circulate the circadian rhythms, which had been discovered a while ago. So, I think there's definitely an impact and we're just beginning to understand why this is and what regulates it. Cindy St. Hilaire:              Yeah, that segues nicely into the next thing I was wondering about and that is we all know not enough sleep, you get tired, your brain's not focused and stuff like that, but it really does impact the inflammatory system and also cardiovascular disease. So how is sleep involved in this innate immunity cardiovascular disease progression? Matthias Nahrendorf:    The way we approached this was actually thinking about lifestyle factors and their impact on cardiovascular disease. Maybe a decade ago, Fil, who's our middle author on this Review, and I started thinking about lifestyle factors and what struck us is that the association of some of these risk cardiovascular events is really high. So, if you look at sleep or if you look at psychosocial stress, psychosocial stress has an odds ratio of 2.4 for premature myocardial infarction. That is right on scale with all these powerful risk factors that everybody knows about like hypertension, but then what isn't really clear or maybe not entirely, is whether or not these risk factors also act via the innate immune system and that's where we were coming from.                                            I think at this point it's pretty clear that they do have an influence via the immune system. What I think what we've done is we uncovered a couple mechanisms that lead to the activation or dampening of inflammation depending on what you look at, but we don't really understand the broader network. I think there's a lot of work to be done looking into these pathways, which is exciting because I think that we can learn from nature what's dangerous and what's helpful. That this is how humans learn to fly. So, I think that observing what leads to cardiovascular disease, which behaviors are really harmful, will maybe lead us to new ways of mitigating it. Cindy St. Hilaire:              Yeah. Also, I think all of this, it's interesting. We all went after smoking for decades, stop smoking, reduce cardiovascular risk and maybe it's stress and sleep is the next smoking. Matthias Nahrendorf:    Smoking was so successful, right? I mean if you look 50 years back, it was promoted as this healthy thing that you should do. Then people really started to learn how bad it is and now we're at a time where smoking is declining and has declined and we see the results. Lung cancer is really on the decline. So, I think that's a good example how understanding health effects of behavior can be really helpful. Maximilian Schloss:        I think one thing I would like to add is when you ask more general question about innate immunity and when we talk about sleep and sleeping habits, I think what's generally quite interesting to know is that the immune system or these leukocyte numbers in circulation, they oscillate quite dramatically over the course of a day in a healthy human being and also in mouse models. I think one aspect also among others to consider is when we have unhealthy steeping habits, like for example, going to bed late or being a shift worker, drinking for example before going to bed. Then this will also confuse a system on the circadian entrainment, which then subsequently will lead to other problems.                                            I also think another thing is that what you were mentioning with the fasting is what we learned from this similar to these extreme circadian patterns seen when we fast or when a mouse is fasting, then monocyte levels drop into extreme low levels and these monocytes hone back into the bone marrow. I think this is interesting because it shows how dynamic actually a system like innate immune cells actually is. So, it's a very delicate system which responds to sleep disruption, exercise, diets in a very dramatic way. Cindy St. Hilaire:              All right, I'm going to bed early tonight and eating a good dinner. Well, this was a wonderful Review. I really enjoyed reading it. I really do think it's introducing the next targets that we have to go after in modifying cardiovascular disease. Thank you so much for taking the time to speak with me today. Matthias Nahrendorf:    Thank you. Maximilian Schloss:        Thank you so much. Cindy St. Hilaire:              That's it for our highlights from the March 27th and Compendium issue of Circulation Research. Thank you so much for listening. This podcast is produced by Rebecca McTavish, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for highlighted articles was provided by Ruth Williams. Thank you to our guests, Max Schloss and Matthias Nahrendorf. I'm your host, Dr. Cindy St. Hilaire, and this is Discover CircRes, your on the go source for the most up-to-date and exciting discoveries in basic cardiovascular research.  

Emily Baum's The Invention of Madness: State, Society, and the Insane in Modern China, published by the University of Chicago Press in 2018 as part of the Studies of the Weatherhead East Asian Institute book series, is a genealogy of “psychiatric modernity,” of the invention and reinvention of modern mental illness in Beijing, 1901-1937. Focusing on the pivotal roles of the city's police-run municipal asylum and the Peking Union Medical College, Baum chronicles the transition from eclectic but largely family-centered premodern apprehensions and treatments of “mad behaviors” to a more unified, biomedical, institutionalized view of madness that was intimately linked to questions of social control, political legitimacy, and the rubric of “mental hygiene.” Along the way, this history of neuropsychiatry's penetration of the administrative and social fabric of modern China examines topics including disjunctures between state and civil actors concerning new understandings and practices around mental illness, as well as the “psychiatric entrepreneurs” who profited from—and sometimes helped to invent or define—new psychiatric conditions. Baum's careful unearthing of these tensions and innovations sheds informative light on the ways in which madness was invented not just as a top-down administrative or biomedical-neuropsychiatric project but in negotiation with a wide range of actors. Learn more about your ad choices. Visit megaphone.fm/adchoices Support our show by becoming a premium member! https://newbooksnetwork.supportingcast.fm/psychology

Emily Baum’s The Invention of Madness: State, Society, and the Insane in Modern China, published by the University of Chicago Press in 2018 as part of the Studies of the Weatherhead East Asian Institute book series, is a genealogy of “psychiatric modernity,” of the invention and reinvention of modern mental illness in Beijing, 1901-1937. Focusing on the pivotal roles of the city’s police-run municipal asylum and the Peking Union Medical College, Baum chronicles the transition from eclectic but largely family-centered premodern apprehensions and treatments of “mad behaviors” to a more unified, biomedical, institutionalized view of madness that was intimately linked to questions of social control, political legitimacy, and the rubric of “mental hygiene.” Along the way, this history of neuropsychiatry’s penetration of the administrative and social fabric of modern China examines topics including disjunctures between state and civil actors concerning new understandings and practices around mental illness, as well as the “psychiatric entrepreneurs” who profited from—and sometimes helped to invent or define—new psychiatric conditions. Baum’s careful unearthing of these tensions and innovations sheds informative light on the ways in which madness was invented not just as a top-down administrative or biomedical-neuropsychiatric project but in negotiation with a wide range of actors. Learn more about your ad choices. Visit megaphone.fm/adchoices

Emily Baum’s The Invention of Madness: State, Society, and the Insane in Modern China, published by the University of Chicago Press in 2018 as part of the Studies of the Weatherhead East Asian Institute book series, is a genealogy of “psychiatric modernity,” of the invention and reinvention of modern mental illness in Beijing, 1901-1937. Focusing on the pivotal roles of the city’s police-run municipal asylum and the Peking Union Medical College, Baum chronicles the transition from eclectic but largely family-centered premodern apprehensions and treatments of “mad behaviors” to a more unified, biomedical, institutionalized view of madness that was intimately linked to questions of social control, political legitimacy, and the rubric of “mental hygiene.” Along the way, this history of neuropsychiatry’s penetration of the administrative and social fabric of modern China examines topics including disjunctures between state and civil actors concerning new understandings and practices around mental illness, as well as the “psychiatric entrepreneurs” who profited from—and sometimes helped to invent or define—new psychiatric conditions. Baum’s careful unearthing of these tensions and innovations sheds informative light on the ways in which madness was invented not just as a top-down administrative or biomedical-neuropsychiatric project but in negotiation with a wide range of actors. Learn more about your ad choices. Visit megaphone.fm/adchoices

Emily Baum’s The Invention of Madness: State, Society, and the Insane in Modern China, published by the University of Chicago Press in 2018 as part of the Studies of the Weatherhead East Asian Institute book series, is a genealogy of “psychiatric modernity,” of the invention and reinvention of modern mental illness in Beijing, 1901-1937. Focusing on the pivotal roles of the city’s police-run municipal asylum and the Peking Union Medical College, Baum chronicles the transition from eclectic but largely family-centered premodern apprehensions and treatments of “mad behaviors” to a more unified, biomedical, institutionalized view of madness that was intimately linked to questions of social control, political legitimacy, and the rubric of “mental hygiene.” Along the way, this history of neuropsychiatry’s penetration of the administrative and social fabric of modern China examines topics including disjunctures between state and civil actors concerning new understandings and practices around mental illness, as well as the “psychiatric entrepreneurs” who profited from—and sometimes helped to invent or define—new psychiatric conditions. Baum’s careful unearthing of these tensions and innovations sheds informative light on the ways in which madness was invented not just as a top-down administrative or biomedical-neuropsychiatric project but in negotiation with a wide range of actors. Learn more about your ad choices. Visit megaphone.fm/adchoices

Emily Baum’s The Invention of Madness: State, Society, and the Insane in Modern China, published by the University of Chicago Press in 2018 as part of the Studies of the Weatherhead East Asian Institute book series, is a genealogy of “psychiatric modernity,” of the invention and reinvention of modern mental illness in Beijing, 1901-1937. Focusing on the pivotal roles of the city’s police-run municipal asylum and the Peking Union Medical College, Baum chronicles the transition from eclectic but largely family-centered premodern apprehensions and treatments of “mad behaviors” to a more unified, biomedical, institutionalized view of madness that was intimately linked to questions of social control, political legitimacy, and the rubric of “mental hygiene.” Along the way, this history of neuropsychiatry’s penetration of the administrative and social fabric of modern China examines topics including disjunctures between state and civil actors concerning new understandings and practices around mental illness, as well as the “psychiatric entrepreneurs” who profited from—and sometimes helped to invent or define—new psychiatric conditions. Baum’s careful unearthing of these tensions and innovations sheds informative light on the ways in which madness was invented not just as a top-down administrative or biomedical-neuropsychiatric project but in negotiation with a wide range of actors. Learn more about your ad choices. Visit megaphone.fm/adchoices

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.                                                 What do salty, Chinese meals, neurotransmitters, cancer, and pulmonary arterial hypertension have in common? Well, you are not going to want to miss this week's feature discussion. It's going to reveal a new therapeutic approach to pulmonary arterial hypertension that may just surprise you, coming up right after these summaries.                                                 Do congenital heart defects signal a familial predisposition to cardiovascular disease? Well, this question was addressed in this week's first original paper from first and corresponding author, Dr. Auger, from University of Montreal Hospital Research Center in Quebec, Canada. Dr. Auger and colleagues aimed to determine whether the risk of cardiovascular disorders later in life was higher in women who had newborns with congenital heart defects. To answer the question, they studied a cohort of more than one million women who had delivered infants between 1989 and 2013 in Quebec. They showed for the first time that congenital heart defects in offspring were associated with increased risk of maternal cardiovascular morbidity later in life, including atherosclerotic disease, cardiac hospitalization, and cardiac transplantation. The association with subsequent cardiovascular morbidity risk was present for both critical and noncritical congenital heart defects. Thus, women who have given birth to offspring with congenital heart defects may benefit from early attention to traditional cardiovascular risk factors and more aggressive primary prevention strategies.                                                 Acute myocardial infarction, or AMI, is a major cardiovascular complication of non-cardiac surgery, but what are the outcomes following perioperative AMI? This question was answered in the next paper from co-corresponding authors, Dr. Smilowitz and Berger, from New York University School of Medicine. The authors identified more than 8,000 patients who were diagnosed with AMI during hospitalization for major non-cardiac surgery using the 2014 US Nationwide Readmission Database. They found that perioperative AMI after non-cardiac surgery was associated with a high in-hospital mortality and a 19% risk of 30-day hospital readmission among survivors. The majority of hospitalizations after perioperative AMI were because of infectious, cardiovascular, or bleeding complications. Recurrent AMI occurred in 11% of patients re-hospitalized after perioperative AMI. At six months after perioperative AMI, more than 36% of patients were re-hospitalized, and the overall risk of in-hospital deaths was almost 18%. Thus, hospital readmissions and mortality among patients with perioperative AMI pose a significant burden to the healthcare system. Strategies to improve outcomes of surgical patients early after perioperative AMI are warranted.                                                 What is the recent status of hypertension in China? Co-corresponding authors, Dr. Wang and Gao, from Fuwai Hospital, Peking Union Medical College, and Chinese Academy of Medical Sciences in China used a stratified, multistage, random sampling method to obtain a nationally representative sample of more than 450,000 residents from 31 provinces in mainland China from 2012 to 2015. The authors found that more than 23% of Chinese aged 18 years or old had hypertension, and that's equivalent to an estimated 284.5 million individuals. The prevalence of hypertension was similar in rural and urban settings, whereas three municipalities, mainly Beijing, Tianjin, and Shanghai had the highest prevalence of hypertension. Almost half the hypertensive population was aware of their hypertension. About 41% were treated, and only 15% achieved a blood pressure control. Among treated patients, barely 32% were prescribed two or more antihypertensive medications. Thus, this study revealed a considerable prevalence of hypertension in Chinese adults, as well as low awareness and control rates, representing an urgent public health message in China.                                                 Patients with systemic sclerosis-associated pulmonary arterial hypertension have a far worse prognosis than those with idiopathic pulmonary arterial hypertension. But why is this the case? In the next paper, from co-corresponding authors, Dr. Hsu and Dr. Kass, from Johns Hopkins University School of Medicine, these authors tested whether the disparity involved underlying differences in myofilament function. They studied cardiac myocytes isolated from the right ventricular septal endomyocardial biopsies from patients with systemic sclerosis-associated pulmonary arterial hypertension, idiopathic pulmonary arterial hypertension, or systemic sclerosis with exertional dyspnea but without pulmonary arterial hypertension. They also looked at control right ventricular septal tissue obtained from non-diseased donor hearts.                                                 They found that right ventricular myofilaments isolated from humans with systemic sclerosis-associated pulmonary arterial hypertension exhibited diminished contractile force and abnormal calcium sensitivity versus control myofilaments. This is in sharp contrast to the hypercontractile compensation in idiopathic pulmonary arterial hypertension. Systemic sclerosis patients with dyspnea and only exercise-induced pulmonary hypertension exhibited an intermediate right ventricular myocardial filament phenotype. These myofilament contractile abnormalities correlated strongly with in vivo right ventricular function at rest and right ventricular contractile reserve during exercise, suggesting a central role of right ventricular myofilament dysfunction in systemic sclerosis-associated pulmonary arterial hypertension.                                                 In summary, these findings uncover key deficiencies in the right ventricles of systemic sclerosis-associated pulmonary arterial hypertension, and these findings suggest that therapies targeted at right ventricular myofilament contractile dysfunction may prove particularly useful for this vulnerable subpopulation. That wraps it up for our summaries. Now, for our feature discussion.                                                 Today's feature paper promises a new therapeutic approach in pulmonary arterial hypertension. We know that pulmonary arterial hypertension is a rare disease, but nonetheless it casts a large shadow because it most commonly afflicts young women and remains a disabling disease. Despite treatment advanced in the last 20 years, high-risk patients still succumb at a rate of 15% annually. Moreover, our most effective therapy is a continuous infusion of parenteral prostacyclin, which is both cumbersome and expensive. Thus, there remains an urgent need for better therapies to improve survival and quality of life. Today's feature paper introduces a novel approach to this.                                                 I'm so pleased to have the corresponding author, Dr. Sylvia Cohen-Kaminsky, from Inserm, Paris, France, as well as associate editor Dr. Charlie Lowenstein, from University of Rochester, to discuss today's special paper. You know, I'm gonna start with Charlie, because you have a way of explaining things and just putting the background to mechanistic papers so well. Could you do that for us, please? Dr Charlie Lowenstein:  Sure. When I started in research, I worked in a neuroscience laboratory. One of the things we studied was glutamate and its class of receptors. Glutamate, as you know, is one of the major neurotransmitters in the brain. The brain releases small amounts of glutamate, which acts as a messenger, neurons talking to other neurons. But when there's a stroke, the brain releases huge amounts of glutamate, and it's actually toxic and can cause damage, and mediate neuronal damage and cell death. Glutamate is a hot topic in the world of neuroscience. But in the cardiovascular field, people don't know much about glutamate. They don't appreciate glutamate as being important at all. So, I have a question for you, Sylvia. How did you start to get interested in glutamate and its family of receptors? Dr Sylvia Cohen-Kaminsky:          It started around 2000, and since 2000 we are having some clues about peripheral glutamate receptor in different cells in different organ. But basically, for vascular cells and for the topic of PAH, there was two things that make me thought about it. First of all, it was shown that the NMDA receptor contributes to the proliferation of different cancer cell types. Human tumor cells express the NMDA receptor, then an NMDA-receptor antagonist may inhibit cancer cell growth and migration. We know that pulmonary vascular cells from PAH patients have cancer-like properties. They are also proliferative and resistant to apoptosis, and they have several properties of cancer cells, such as metabolic shift and so on.                                                 In addition, not only neurons in the brain express the NMDA receptor, but also brain microvascular endothelial cells that respond to an NMDA receptor activation by gross production, disruption of endothelial cell barrier, and monocyte transmigration. All these three processes are relevant to PAH development. That's why I thought that perhaps an NMDA receptor is expressed on microvascular cells from the lung, and perhaps we could have a process involving an NMDA receptor in this vascular remodeling. Dr Charlie Lowenstein:  As you know, there are three flavors of glutamate receptors. How did you discover that there was one particular kind, the NMDA receptor, that was really important for smooth muscle cells? Dr Sylvia Cohen-Kaminsky:          You are right. We did analysis of mRNA expression, and most of the known receptor in the brain, either metabotropic or ... ionotropic, sorry, indeed expressed in vascular cells and they may cooperate to activate this NMDA receptor exactly as it happens in the brain. We didn't work that on these other receptor, but we are pretty sure they are at work in cooperation with the NMDA receptor. Why though an NMDA receptor? Because it's an ion channel permeable to calcium, and the calcium is an event which can be important in cell proliferation. In addition, the first thing we have shown in these remodeled vessels when we did mass spectrometry imaging was increased level of glutamate and glutamine, its precursor. That was also an additional element that makes us think about this NMDA receptor. Dr Charlie Lowenstein:  I want to go from the receptor to glutamate. There are three or four amazing things about your paper. One of them is that you suggest that cells in the vascular are releasing glutamate, which is a neurotransmitter. Do you think those are the smooth muscle cells that are talking to other smooth muscle cells by releasing these messenger molecules? Dr Sylvia Cohen-Kaminsky:          Yes. Smooth muscle cells are talking to other smooth muscle cells. But we also did some work on endothelial cells, and they are also able to release this glutamate. So we think that vascular cells in the vascular wall are discussing together through glutamate, although we don't know yet the normal function of this NMDA receptor in the vascular system. However, in the pathology it's very clear that there is this release. What is very interesting is that this release can be triggered by pathways which are already down-regulated in PAH, such as the endothelin-1 pathway. Dr Charlie Lowenstein:  Another remarkable part of your observation is that the signaling with glutamate and glutamate receptors is hyperactivated in the setting of a major human disease, pulmonary artery hypertension. How did you figure out that glutamate is so important in this special disease? Dr Sylvia Cohen-Kaminsky:          Because we showed, as I already told you, this glutamate accumulation in the remodeled vessel. We used this mass spectrometry imaging which allows analysis of metabolites directly in the remodeled vessels from sections performed from extended lengths. We saw this glutamate accumulation together with glutamine accumulation, so the ligand was overexpressed. In addition, when doing western blots from these remodeled tissue dissected from ongoing arteries, we have shown that we have a particular phosphorylation of this receptor which is very well-known in the CNS. This phosphorylation is involved in sending the receptor to the membrane and stabilizing the receptor to the membrane. Having this phosphorylation means that NMDA receptor is engaged, activated in the remodeled vessels in situ. Dr Charlie Lowenstein:  In an experimental model, you explored the role of glutamate in two very nice, complementary ways. One is with a genetic approach, the NMDA receptor deficiency. The other is using drugs. What were the drugs, what were the pharmacology that you used to block glutamate's transmission, and how did that affect the mice? Dr Sylvia Cohen-Kaminsky:          We used drugs that are very well known in the CNS. We used two drugs. One is memantine, which is already commercialized for the treatment of Alzheimer's disease. The other one is MK-801, which has been produced initially as a potential pharmacological drug but it was too potent to be used in the CNS. Therefore, this drug is only used in research at the moment. But these two drugs were able to act on this vascular remodeling and a number of PAH parameters. We have explored at least 12 parameters involved in this animal model of PAH, and hemodynamic stable parameters of hemodynamics including intra-arterial pressure, vascular remodeling, right ventricular remodeling with different parameters that shows a certain index. The cardiomyocyte hypertrophy, the fibrosis, the inflammation inside the right heart and around remodeled vessels, all these parameters were modified by the drug.                                                 In addition, in vivo we have shown the destruction of the NMDA receptor glutamate axis with decreased engagement of the NMDA receptor in pulmonary arteries by following this phosphorylation I mentioned, decrease of apoptosis resistance and also proliferation. This was shown also after the treatment with the drugs, and also decrease of endothelial cell dysfunction that could be followed in the blood through selecting those H. Dr Charlie Lowenstein:  Your results with this drug were really impressive. I love that part of your study. You showed when you block glutamate signaling, first of all, the blood vessels looked much better in a model of pulmonary artery hypertension. In an experimental model, blocking glutamate transmission really improved the way the vessels look. But secondly, what was really amazing was, normally in humans one of the big problems with pulmonary artery hypertension, as you said, is the right ventricle gets inflamed and fibrotic, and a lot of patients die from complications of right ventricular dysfunction. In your model, when you treat with MK-801, blocking glutamate receptor, the right ventricle looks a lot better. It was really an impressive part of your study. Dr Sylvia Cohen-Kaminsky:          I think that this is view on the effect of the vessels themselves, then the right heart can recover. But we may have a direct effect in the heart. If you remember this Chinese restaurant syndrome, when you eat too much Chinese food, which is full of glutamate, you have some cardiac involvement, arrhythmia, and so on. Initially, toxicologists thought that it passed through the central nervous system. But then they realized that maybe the NMDA receptor is expressed in cardiac cells, and indeed it is expressed and is colocalized with the ryanodine receptor, meaning that it could have a function in the heart as well. But this has, of course, to be explored precisely. We know from the transplantation that, when we transplant on with the lung, the heart can recover very well. We may have these two effects. One due to the relief on vascular remodeling, and the other perhaps a direct effect on the heart. Dr Carolyn Lam:                You know, I have to chime in now. That cuts too close to home with the Chinese food and glutamate. First and foremost, I just really have to say, Charlie and Sylvia, it's people like you who make basic science come alive and simply extraordinarily exciting. Taking glutamate, something that we've talked about in the context of Chinese food and neurotransmitters, and therefore showing the potential to even repurpose perhaps some drugs for pulmonary arterial hypertension. So let me just round up by asking you, what do you think our next steps, how far are these findings away from clinical application? Perhaps, Charlie, your thoughts? Dr Charlie Lowenstein:  While I think that the use of MK-801 to treat excess monosodium glutamate during a Chinese meal, maybe that's a little bit premature. I'm much more excited about the idea of using glutamate-receptor antagonists to treat or prevent or even reverse pulmonary artery hypertension, both its vascular and cardiac complications. I'd love to ask Sylvia, do you think these medications in this class, do you think NMDA-receptor antagonists are ready for clinical trials? Dr Sylvia Cohen-Kaminsky:          In fact, they are not ready as they are. We have a program in which we have designed hypothesized new NMDA-receptor antagonist that do not go to the brain, because we want that treating PAH has to be safe, and we don't want to interfere with brain system. So we created this new NMDA-receptor antagonist that do not go to the brain. At the moment, we are in the process of the documentation. We have two patents for two series of molecules, and we expect the drug conjugate by the end of this year. To reconjugate means that we have a number of properties on this drug, the pharmacokinetics, metabolism, selectivity profile, toxicity, and so on. We are doing all this physical chemical properties, and of course validation of these new molecules in the animal models as therapy alone and also as add-on therapy with existing therapies, such as these vasodilators. We hope that we can have an additive effect between an NMDA-receptor antagonist and current PAH drugs. Dr Charlie Lowenstein:  Sylvia, as you know, drug companies about 10 or 20 years ago invented all these amazing glutamate-receptor antagonists to treat central nervous disease like stroke. One of the amazing things about your discovery is you're suggesting that glutamate receptors in the periphery are great targets as well. The exciting thing about your observation is you're really opening up new therapeutic approaches for targeting neurotransmitters in the periphery. I think your discoveries are tremendously exciting and could open up new avenues in treatment of a disease, pulmonary artery hypertension, for which there really aren't effective therapies right now. Dr Carolyn Lam:                I couldn't have said it better. Thank you so much, Charlie. Thank you so much, Sylvia.                                                 See, listeners? Aren't you glad you heard it here right on Circulation on the Run? Don't forget to tune in again next week.  

Dr Carolyn Lam:                Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Our featured discussion today centers on the challenges of cardiovascular disease risk evaluation in people living with HIV infection, an important discussion coming right up after these summaries.                                                 The first original paper this week provides experimental evidence that nicotinamide riboside could be a useful metabolic therapy for heart failure. First author Dr. Diguet, corresponding author Dr. Mericskay, from University Paris-Sud investigated the nicotinamide adenine dinucleotide or NAD homeostasis pathways in the failing heart. They found that an expression shift occurs in both murine and human failing hearts in which the nicotinamide riboside kinase two enzyme, which uses the nucleoside nicotinamide riboside was strongly up-regulated for NAD synthesis.                                                 Nicotinamide riboside supplemented diet administered to murine models of dilated cardiomyopathy or pressure overloaded induced heart failure restored the myocardial NAD levels and preserved cardiac function. Nicotinamide riboside increased glycolysis as well as citrate and Acetyl-CoA's metabolism in these cardiomyocytes. Thus, nicotinamide riboside supplemented diet may be helpful in patients suffering from heart failure and may help them to cope with the limited myocardial ATP supply by restoring NAD coenzyme levels and its associated signaling.                                                 In the single ventricle reconstruction trial, one year transplant-free survival was better for the Norwood procedure with the right ventricle to pulmonary artery shunt compared with the modified Blalock‒Taussig shunt in patients with hypoplastic left heart and related syndromes. In the paper in this week's journal, authors compare transplant-free survival and other outcomes between these groups at six years. First and corresponding author Dr. Newburger from Children's Hospital Boston and her group showed that the right ventricular pulmonary artery shunt group had similar transplant-free survival at six years, but required more catheter interventions before the Fontan procedure.                                                 Right ventricular ejection fraction, New York Heart Association class and complications did not differ by shunt time. Cumulative incidences of morbidities by six years included 20% with a thrombotic event, 15% with a seizure, and 7.5% with a stroke. These data therefore emphasize the importance of continued follow-up of the cohort, and the need to find new strategies to improve the long-term outlook for those with single ventricle anomalies.                                                 The next paper presents results of the CREATIVE trial, which stands for Clopidogrel Response Evaluation and Anti-Platelet Intervention in High Thrombotic Risk PCI Patients). First and corresponding author Dr. Tang from Fuwai Hospital National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College conducted a head-to-head comparison of the safety and effectiveness of intensified anti-platelet therapies either a double dose clopidogrel or adjunctive cilostazol and conventional strategy in 1078 post-PCI patients at high thrombotic risk as identified thromboelastography, which is a platelet function test.                                                 The primary outcome was the incidence of major adverse cardiac and cerebral vascular events at 18 months post-PCI they find as a composite of all cause death, myocardial infarction, target vessel revascularization, or stroke. The authors found that the primary end point occurred in 14.4% of those in the conventional strategy. 10.6% in those given double dose clopidogrel alone. And 8.5% in those also given adjunctive cilostazol. Now, although both intensified anti-platelet strategies achieved increased platelet inhibition, only the triple strategy with adjunctive use of cilostazol significantly reduced adverse events in the long-term follow-up.                                                 No increased rates of major bleeding was found with the intensified anti-platelet therapy regimes. Thus, in patients with low responsiveness to clopidogrel as measured by thromboelastography, the intensified anti-platelet strategies with adjunctive use of cilostazol significantly improved the clinical outcomes without increasing the risk of major bleeding.                                                 The final original paper sheds light on the prevalence and predictors of cholesterol screening awareness and statin treatment among American adults with familial hypercholesterolemia or other forms of severe dyslipidemia. First and corresponding author Dr. Bucholz from Boston's Children's Hospital and their colleagues used data from the National Health and Nutritional Examination Survey, and showed a high prevalence of screening and awareness above 80%. However, there were relatively low rates of statin use among individuals with familial hypercholesterolemia at 52.3%.                                                 And even lower rates among those with severe dyslipidemia at 37.6%. The discrepancy between the prevalence of cholesterol screening and treatment was most pronounced in younger patients, uninsured patients, and patients without a usual source of healthcare. This study highlights an imperative to improve the frequency of cholesterol screening and statin prescription rates to better identify and treat this high risk population. Additional studies are needed to better understand how to close these gaps in screening and treatment.                                                 And that brings us to the end of our summaries. Now for our feature discussion. The natural history of infection with HIV has completely changed with the use of potent antiretroviral therapies. We now know that people living with HIV actually have morbidity and mortality patterns that really resemble the general population, especially with regards to cardiovascular disease, which is very prominent in this population. And I suppose it's this that has led to the assumption perhaps that risk prediction tools and intervention strategies that we apply in the general population may be used in patients living with HIV.                                                 Is this the case however? Well, this week's feature discussion is going to be so enlightening. And it's so important we are talking across the world here, from South Africa to the United States, and of course with me here in Singapore. I am so pleased to have the authors of this week's feature paper and they are none other than Dr. Virginia Triant from Massachusetts General Hospital, Dr. Ralph D'Agostino from Boston University. And our associate editor, Dr. Bongani Mayosi from University of Cape Town. Thank you so much for joining me for today's exciting discussion. Virginia, could I ask you to first describe your study? Dr Virginia Triant:             As you mentioned in the introduction, we have found that patients infected with HIV have an increased risk of cardiovascular disease. That includes both myocardial infarction and stroke compared to age-matched controls in the general population. And extensive data has suggested that the etiology of this increased risk is related both to traditional cardiovascular risk factors, as well as novel risk factors that are specific to HIV infection. And these include chronic inflammation in the immune activation. So consequently, it remains relatively unknown whether established cardiovascular risk prediction functions are accurate for patients with HIV because they include only risk factors that are traditional factors and they don't reflect the complete mechanism that we know is at play in cardiovascular disease associated with HIV.                                                 So in our study, we assess the performance of three established cardiovascular risk prediction functions, two Framingham functions, and then the ACC/AHA pooled cohort's equations and we applied this to a longitudinal HIV infected cohort that was comprised of men. And we investigated the performance of the risk scores in terms of comparing regression coefficients, discrimination and calibration, which are standard metrics in cardiovascular risk prediction. So I'll briefly summarize our overall results as a start. We found that overall, the risk prediction functions underestimated risk in our group of HIV-infected men.                                                 We found that discrimination was modest to poor, and this was indicated by low c-statistics for all of the equations. And we also found that the calibration or the agreement between observed or predicted risk was also poor across the board for all three risk prediction functions. So our results suggests that simply taking the risk prediction functions and transporting them to an HIV infected group may actually result in mis-classification in terms of patient risk. And in underestimation of cardiovascular risk. Dr Carolyn Lam:                Well, Virginia, beautifully summarized of a beautiful paper. But perhaps at this point, we should take a step back and ask ourselves how exactly were these risk prediction scores originally developed. And I can't imagine asking a better person than Ralph. Ralph, could you take us on a jaunt along history and tell us how were those Framingham risk scores developed in the first place? Who are they supposed to be applied to? And did these results surprise you? Dr Ralph D'Agostino:      After the second World War, what was becoming quite clear is things like cardiovascular disease were becoming very prominent. Things like infections and what have you, we were developing all sorts of ways of handling them with medicines and so forth. But with cardiovascular disease, it's a thing that progresses slowly over the years and it starts wiping out people. And back in those days, one out of three men between the ages of 30 and 60 had some kind of cardiovascular event. Women weren't that bad off, but they were pretty bad off also. And so what happened is the American government and the American Heart Institute set up this study in Framingham, where they took a third of the individuals between the ages of 30 and 60 and actually followed them. They took values of variables like blood pressure, cholesterol, things they thought might be useful.                                                 And took values on them. And they had to come back every two years and after as time went on, they took the data after six years, after 10 years they took the data, and started to look at how each individual's blood pressure related to cardiovascular disease. Does cholesterol, and the answer was yes. And then I started getting involved and we were developing these cardiovascular functions where you could actually take an individual, take their measurements now, and make a prediction that had a lot of validity, good discrimination, high predictability over what was going to happen in ten incidents and then the government, the US Government, started having guidelines and what we did is we ran a study where we took a number of different studies in the US, different cardiac studies, the ARIC studies, number of 'em, and we thought applying our functions how well would they do. And it turned out that for whites in the country, the Framingham functions did very well.                                                 But Japanese-Americans in the country, it over-predicted. Then we found out that you could make a calibration adjustment and what we've gone to, like in China, we have a big study where we had a function and Framingham function it over-predicted but calibration adjustment would make enough corrections and so now with Jeanne and the HIV, our hope was that you could take these functions and see how they work on the HIV population. When we did it we were quite well aware, because people have been looking at different things, there's something beyond the original cardiovascular risk. And what the paper shows, quite nicely, these cardiovascular risks do have some relationship but they don't explain enough. The HIV population have a much bigger burden and a simple calibration adjustment just isn't going to work. We need new variables, we need new insights on what to add to these functions. Dr Carolyn Lam:                Thank you so much for that. That's just such important part of history because I have to thank you for those equations. We apply those definitely in our Asian cohorts with that calibration factor. But I was just reflecting as you were telling that story of how we've come full circle now to actually talk about an infection again. It's the midst of an infection, like HIV infection, that we're now testing these equations once again. What better than to ask than Bongani, you're in the epicenter, if I may, of HIV infection. What do you think of the applicability of these findings to the patients you see? Dr Bongani Mayosi:         Yes. These findings are clearly of great interest to us here in the Sub-Saharan African region because it is really the epicenter HIV pandemic. We found population, in terms of risk factors for arteriosclerosis disease still remains low although there clearly derives, for example, in the incidence of myocardial infarction that's being detected in a number of the leading centers now. And with HIV we have observed cases of myocardial infarction while they tend to be younger men who almost always smoke and who get a lot more of a thrombotic episodes.                                                 When you catch them on a thrombotic load, you do not find arteriosclerosis disease. It's going to be important, I think, as we move forward to make sure that as we develop risk functions that will predict cardiovascular disease in patient HIV that the African epidemiological context is completed teaching that HIV affects younger people, affects large numbers of women, but that, quite clearly, is associated with decreased cardiovascular event and stroke and stroke is well demonstrated. But in terms of actually looking at the risk factor this population was still in the early day and certainly in future studies would have to have a major contribution of the African cohort. Dr Carolyn Lam:                That's true, Bongani, but may I ask how would you, perhaps, advise your African colleagues now to look at these data? Then I'd also like to turn that same question over to you, Virginia. What do we do? What's the clinical take home message of these findings? Dr Bongani Mayosi:         I think the message is true that HIV infection is associated with the increased risk of cardiovascular event, there's no doubt about that. That there are some risk factors that can carry through, such as the smoking population but it's important for all clinicians to be aware of that. The ordinary risk you find in using Framingham and other established risk functions is not going to give us all the information that we need. So that recommendation should come through we need to know that risk factors are unknown, that they're important and we need to learn more about these patients in order to give us a perfect prediction of what will happen in the future. Dr Virginia Triant:             I think the findings have a lot of clinical relevance. This suggests, I think, that there are a lot of clinical implications for any patient who has novel cardiovascular risk factors that may not be accounted for in heart functions. And what our findings suggest is that if functions don't reflect the actual composition of risk factors in the population, that can result in misclassification and thus we underestimate risk, we might miss high-risk individuals, high-risk patients who would benefit from aggressive risk reduction but are not currently receiving it. This is a real clinical challenge as sit in clinic and we pull up the scores and calculate them for our patients, whether that is a trustworthy number or whether we should, perhaps, thinking that it's higher, thinking that it's different than what we're seeing for predicted 10-year risk. I think what this suggests is that the functions may need to be further tailored to different populations and sub-populations to reflect the actual composition of risk factors in that population. Even within HIV patients and populations, the risk factors in South Africa might be different than those in Boston, with different relative contributions.                                                 One of the next stepped planned for our team is to actually look at developing, new risk functions which are tailored to HIV and incorporating both HIV itself as a risk factor, as well as HIV specific variables and to attempt to see if we can improve the performance of these functions for HIV populations. Perhaps HIV or HIV related factors might become sort of a new cardiovascular risk equivalent and we can serve patients in this population as higher cardiovascular risk baseline. I also just wanted to mention, briefly, that I think that there are important clinical implications beyond HIV that extend to other chronic inflammatory conditions. Inflammation is increasingly recognized as important in cardiovascular risk and this way HIV can serve as a prototype population. But these results are likely to extend to a lot of different populations who have chronic inflammation for different reasons. Dr Carolyn Lam:                That's a great point, Virginia. As I'm listening, I'm wondering is there no end to this because now we say HIV and then we put other inflammatory diseases, then we say, "Well, women may be different from men," and then different ethnicities may be different. I think gonna be going closer and closer to precision risk prediction, if I might say. Could I just pick your brain here? What do you think the future is? Where's the room for machine learning approaches for risk prediction, individual almost down to that level? What do you think? Dr Ralph D'Agostino:      I think you're right on target. In some sense, the functions we have there's a sort of massiveness about it, when you come to view this population, back in the 50s and 60s and so forth, cardiovascular disease was such a major ... it still is a major problem ... such a major problem you identify some of the real items like the blood pressure and cholesterol, and you attack and develop functions on that and you'd find that you're affecting positively a huge number of individuals, but now as, like Jeanne was saying, and others have been saying, you start focusing, you've got this massive group of individuals who should have their blood pressure controlled and what have you, but if you go into HIV, you go into a number of other populations and so forth, there are other things that are driving these disease and driving the manifestations of the disease. It isn't that blood pressure isn't important, it's that there's other things that are important. And so it's machine learning and so forth and deep learning that you're gonna have to be dealing with manifestations on very high levels and maybe even get into genetics.                                                 Look in the cancer field ... I do a lot of work with the FDA ... look at the cancer field now; how it's so genetically driven in terms of a lot of the drugs the so-called biomarkers, which are basically driven by uniqueness in populations. I think that's definitely going to be, or is the future of these cardiovascular functions. Dr Carolyn Lam:                Okay audience. You heard it, right here. These are exciting times. In the meantime, thank you so much for this precious, valuable piece of work. Virginia, Bongani, Ralph, it was great having you on the show.                                

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 novel results from the NCDR IMPACT Registry that informs us on risk prediction in patients with congenital heart disease undergoing cardiac catheterization. We'll be taking a deep dive into this right after these summaries.                                                 The first original paper provides pre-clinical data showing that delayed repolarization may underlie ventricular arrhythmias in heart failure with preserved ejection fraction or HFpEF. First author Dr. Cho, co-corresponding authors Dr. Marban, and Cingolani from Cedars-Sinai Heart Institute and their colleagues, induced HFpEF in Dahl salt-sensitive rats by feeding them a high-salt diet from seven weeks of age. They showed that susceptibility to ventricular arrhythmias was markedly increased in rats with HFpEF.                                                 Underlying abnormalities included QTc prolongation, delayed repolarization from down-regulation of potassium currents, and multiple re-entry circuits during ventricular arrhythmias. These findings are consistent with the hypothesis that potassium current down-regulation may lead to abnormal repolarization in HFpEF, which in turn predisposes to ventricular arrhythmias and sudden cardiac death.                                                 The next paper shows that genetic testing can help to identify patients with pulmonary veno-occlusive disease who were misclassified as pulmonary arterial hypertension. Now, heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type II or BMPR2 are the commonest genetic cause of pulmonary arterial hypertension. Whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene or EIF2AK4 gene are described in pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis.                                                 In the current study, first author Dr. Hadinnapola, corresponding author Dr. Morrell, and colleagues from University of Cambridge performed whole genome sequencing on the DNA from 864 patients with pulmonary arterial hypertension, as well as 16 patients with pulmonary veno-occlusive disease all recruited to the NIHR BioResource – Rare Diseases study. They found that 1% of patients with a clinical diagnosis of pulmonary arterial hypertension actually carry the biallelic EIF2AK4 mutations. Patients who are diagnosed clinically with pulmonary arterial hypertension, but who had a transfer coefficient for carbon monoxide of less than 50% predicted and an age of diagnosis of less than 50 years were much more likely to carry these biallelic EIF2AK4 mutation. In fact, the diagnostic yield for genetic testing in this group was 53%.                                                 Radiological assessment alone was unable to distinguish reliably between these patients and those with idiopathic pulmonary arterial hypertension. Importantly, these patients with biallelic EIF2AK4 mutations had a worst prognosis compared to other patients with pulmonary arterial hypertension. Thus in summary, younger patients diagnosed with idiopathic pulmonary arterial hypertension but with a low transfer coefficient for carbon monoxide, have a high frequency of biallelic EIF2AK4 mutations and should be reclassified as pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis. They have a poor prognosis and genetic testing can therefore identify these misclassified patients allowing appropriate management and early referral for lung transplantation.                                                 The next study identifies a novel molecular target for the treatment of pathological cardiac hypertrophy. This target is SIRT2 [inaudible 00:04:33] poorly characterized member of the Sirtuin family of proteins, which is a family of class III NAD-dependent deacetylases that regulate metabolism and age-related diseases including diabetes and cardiovascular diseases. In the current study, first authors Dr. Tang and Chen, corresponding authors Dr. Chen and Liu from the Chinese Academy of Medical Sciences in Peking Union Medical College used wild-type and Sirt2 knockout mice, and showed that SIRT2 protein levels and activity were reduced during pathological cardiac hypertrophy.                                                 SIRT2 deficiency promoted aging and angiotensin II induced pathological cardiac hypertrophy, and blunted metformin-mediated cardioprotective effects. On the other hand, SIRT2 overexpression repressed pathological cardiac hypertrophy. The molecular pathway involved deacetylation of liver kinase B1 at lysine 48 by SIRT2 to activate AMP-activated protein kinase sickling, which prevented hypertrophy of cardiomyocytes. Thus, SIRT2 is a potential target for therapeutic interventions in aging and stress-induced cardiac hypertrophy.                                                 The next study is the largest comparison of the prognostic value of coronary artery calcium with functional stress testing in patients with stable chest pain. In this study from first and corresponding author Dr. Budoff from Los Angeles Biomedical Research Institute and colleagues, authors looked at the PROMISE trial where patients with stable chest pain or dyspnea, and intermediate pre-test probability for obstructive coronary artery disease were randomized to functional testing or anatomic testing.                                                 Their main finding was that these chest pain populations referred for testing had a low event rate and both tests had different strengths. Coronary artery calcium had a high sensitivity for future cardiovascular events whereas functional testing had a high specificity. The clinical implications are that a normal coronary artery calcium score has a very low event rate and perhaps maybe used to avoid further cardiac testing in a stable chest pain population. On the other hand, an abnormal functional test result including information on exercise and symptoms has a moderate prognostic value.                                                 Of note, coronary CT angiography provided better prognostic and discriminatory power than either coronary artery calcium or functional testing. The implications of these important results are discussed in an accompanying editorial by Dr. David Newby from Edinburgh entitled, Can I Have My Cake and Eat It? On that intriguing note, we've come to the end of today's summaries, now for our feature discussion.                                                 For today's feature discussion, we are talking about an increasingly important population that is pediatric and adult patients with congenital heart disease undergoing cardiac catheterization. A little bit out of my usual comfort zone, but then you see, I'm with two spectacular experts today, Dr. Gerard Martin from Children's National Health System in Washington DC, one of the authors of today's feature paper; and Dr. Gerald Greil, Associate Editor from UT Southwestern. Welcome gentlemen. Dr. Gerard Martin:           Thank you Carolyn. Dr. Gerald Greil:                Thank you Carol. Dr. Carolyn Lam:               Gerard, no that would be Dr. Martin. Enlighten people like me who don't think about this every day, why the importance of looking at cardiac catheterization, and adverse outcomes in this particular population? Dr. Gerard Martin:           Carolyn, that's because of the tremendous advances in medicine, and particularly medicine that's dealing with children with congenital heart defects. Cardiac catheterization was once purely a diagnostic study. Now, it's a less invasive definitive treatment option for many of our pediatric and adult patients with congenital heart defects. As you may or may not know, congenital heart defects are the most common birth defects that impact nearly one out of every hundred live births.                                                 As I mentioned, we have these tremendous advances. As a result of that, there are now over a million children living with congenital heart defects. In the USA alone, improvements in care over the past 50 years, there are now more adults than children living with congenital heart defects. Dr. Carolyn Lam:               Wow. Now, I understand. I mean, cardiac catheterization not just meeting diagnostic but therapeutic, and such an important patient population. Tell us about your study? Dr. Gerard Martin:           As we said, cardiac catheterization is now replacing surgery for some of our defects. For some of the more complex defects, catheterization is providing treatments that make the surgery easier. Now in surgery, we've had registries for many years. These registries provided measurement of survival that allow comparison of programs, and we didn't have that ability with cardiac catheterization. The American College of Cardiology developed the IMPACT Registry. That was to solely provide measurements of the outcomes of catheterization procedures in the children and adults with congenital heart disease.                                                 Now, one aspect of the quality of the program is your rate of adverse outcomes; but simply measuring the number of adverse outcomes does not provide enough discrimination to compare programs. I think you can probably imagine that adverse outcomes will increase based upon the complexity of the type of patients you see, or the types of procedures that you might be performing. What we wanted to do was to create a risk standardization tool for our population where we can measure variation and performance between programs. If we can do that, then we can learn from the best performers to improve all the others. Dr. Carolyn Lam:               That's beautifully put. Could you tell us what you found? Dr. Gerard Martin:           Sure. The IMPACT Registry began on about 2011 and has grown from 50 sites to 111 sites in 2017. That's the majority of the sites in the United States that perform cardiac catheterization on children. We have now over 115,000 procedures. What we wanted to do with this is to look at some of the early procedures that were included and to see how adverse events were occurring. When we created the registry though, we used data variables from a previous research study in Boston called the CHARM.                                                 They created a tool to risk standardized outcomes during procedures. They did it by coming up with four categories of procedures, and some four markers of hemodynamic vulnerability. We tested their methodology with IMPACT, and it didn't really performed particularly well. In this study, what we did was to increase the number of risk categories. We took the nearly 200 types of procedures we do in the cath lab and divided them into six categories. We also increased the indicators of hemodynamic vulnerability from four to six.                                                 Now, what I mean by hemodynamic vulnerability? What is the patient's oxygen level when they go into the procedure? What is their blood pressure when they're in the procedure? Do they have one ventricle, or do they have two ventricles? What is the resistance in the lung vessels? All these are critically important. Lastly, we looked at some baseline patient characteristics. In other words, was age important? Sex, genetic conditions, or other comorbid conditions like the level of mechanical support that the patients were on. Then we put all that into our model to see if we could come up with a risk score. Dr. Carolyn Lam:               Right. The final adjustment model? Which factors that they include in the end? Dr. Gerard Martin:           We did find that there are lot of adverse events that do occur. We found major adverse events occurring in about same 7% of our patients. Most common adverse events were bleeding, or rhythm disturbances that require some medicine, or cardioversion during the procedure, or death during the hospitalizations. We did find that these major events were more common in the youngest patients or neonates, children under a month of age, or in patients with genetic disorders, or single ventricle physiology, and also patients that went to the cath lab with their kidneys not working very well.                                                 In the end, we did create a risk adjustment model that included the type of procedure that was done, the number of hemodynamic vulnerability indicators, and whether or not the patient had renal insufficiency, or single ventricle physiology, or coagulation, and we found really good discrimination. Our discrimination had a C-stat of 0.76 in the derivation cohort, and 0.75 in the validation cohort. The slope of the curve was excellent, so we really think we have something now that we can use as a tool. Dr. Carolyn Lam:               Gerald, you're a pediatric cardiologist. Could you give us your perspective on how important these results are? Dr. Gerald Greil:                I think it's the largest and the first study, which kinds of give us a calibration in our field how successful interventions are. How we can make centers better without finger pointing on specific centers, and how to advance the field as a whole? From that perspective, I'm quite excited that the group offered us to publish this paper in circulation. I was kind of asking a question to Dr. Martin because obviously, all essentials are closely monitored. There's obviously data publicly available. Do you think there's a risk that this way to monitor centers within the United States or probably worldwide, that it's potentially preventing innovation or risky procedures? Dr. Gerard Martin:           I think that, that's a good question. I think it's one thing that whenever we talk about transparency or public reporting, it's an argument against it. I think that having a model like this, actually levels the playing field. In other words, centers that are risk averse who aren't particularly innovative, you'll be able to look at those centers, see what type of patients they're doing and look at their adverse events for a low-risk population. Then, you can also look and see some other centers that are doing more complicated procedures, higher risk, and you can see what their adverse event rate is.                                                 Certainly, this is only talking about the adverse events. This has to be put together with the outcome of the procedure. In other words, if you're trying to relieve an obstruction, did you relieve it? Did you meet the intended goal of the procedure? This is only half of the story. The other part of it is, did you get the intended goal of the procedure? When you put the two of them together, perhaps some of those centers that are risk averse have lower complications, but maybe their success rate is lower. This will be able to tell the public everything they know, and they'll be able to tell their providers what they need to know to get better. Dr. Carolyn Lam:               I have to agree. Your paper does highlight, I think. Gerard, just one other question. What do you think our next steps? Dr. Gerard Martin:           The next step is to test the data. We have a new version of IMPACT that has rolled out, version 2 that has new procedures in it. Now, we have to test the data and we actually have to look for variability. Can we see a variation between the programs? Then, once we see if there's variation, if we see there is best performers and those performers that could improve, a question then is how do we take from what the best performers are doing to try and lift those that need to improve up. That's going to be the true hard work for this registry. Dr. Carolyn Lam:               Thank you so much for publishing it with us. Thank you so much audience for listening with us today. Don't forget to tune in again next week.  

Tang’s novels of coming-of-age and contemporary life in Beijing have made him an immensely popular writer whose appeal has endured throughout the years. His first novel Happiness was written at age 18 and he has since written several masterpieces: Given a Chick at Age 18, Ever Since Growth, The Oneness, No Woman No Cry, and Beijing, Beijing. Tang’s literary accomplishments include the short stories: "Pigs and Butterflies," "You Live and Live and Then You're Old," "How to Become a Monster," "36 Biggies of Life,” and a collection of poems entitled One Hundred Poems of Feng Tang. Feng Tang’s 2005 novel, Everything Grows, was adapted into a movie titled Ever Since We Love. His novel Beijing, Beijing will be adapted into a film for worldwide audiences. In addition to his literary accomplishments, Tang possesses over 15 years of experience in corporate management in various sectors and possesses deep knowledge of the healthcare industry. He is a Senior Managing Director of CITIC Capital Partners, founded China Resources Healthcare Group Limited, and was also a partner at McKinsey & Company. Tang received an M.B.A. degree from the Goizueta Business School at Emory University in 2000 and an M.D. degree from Peking Union Medical College in 1998.