European Heart Journal

Nicholls, Mark

doi: 10.1093/eurheartj/ehab634pmid: 34491322

All correspondence relating to this paper should be sent to: [email protected] Professor Zhi-Cheng Jing, Head of the Cardiology Department of Peking Union Medical College Hospital in China, discusses his pioneering work in pulmonary vascular medicine as the hospital marks its 100th Anniversary. The Peking Union Medical College Hospital (PUMCH) has been described as the cradle of cardiology in China. Opened for patients on September 16, 1921, and celebrating its 100th anniversary, it is where the first ECG report in China was signed and has since seen important research breakthroughs and therapies conducted for patients with a range of cardiovascular conditions. Today, Zhi-Cheng Jing (Figure 1) is a Professor of Medicine and Head of Cardiology at PUMCH, the Chinese Academy of Medical Sciences (CAMS), and Peking Union Medical College (PUMC) and immensely proud of his role at the centre and its part in Chinese cardiovascular care—past, present, and future. Figure 1 Open in new tabDownload slide Zhi-Cheng Jing; right (top) three-lead ECG report signed by Dr Peabody on September 30, 1921. Diagnosis: normal ECG. Patient number: 703. ECG number: 0040; right (middle) Prof. Jing and his team adopted balloon pulmonary angiography for the treatment of chronic thromboembolic pulmonary hypertension patients in Shanghai Pulmonary Hospital in 2008; right (bottom) Prof. Jing with Prof. Gérald Simonneau in 2004. Figure 1 Open in new tabDownload slide Zhi-Cheng Jing; right (top) three-lead ECG report signed by Dr Peabody on September 30, 1921. Diagnosis: normal ECG. Patient number: 703. ECG number: 0040; right (middle) Prof. Jing and his team adopted balloon pulmonary angiography for the treatment of chronic thromboembolic pulmonary hypertension patients in Shanghai Pulmonary Hospital in 2008; right (bottom) Prof. Jing with Prof. Gérald Simonneau in 2004. An internationally recognized authority on pulmonary vascular medicine having made a number of discoveries and pioneered treatments for patients, he leads a dynamic team conducting cutting edge therapy and research. Prime Minister or doctor? Born in August 1971 in Qi’men, Anhui Province, a small town famous for its black tea at the foot of the Huang’shan Mountain, his father was a military officer and his mother was a primary school teacher. His family moved to Shan’dong Province when he was seven, where he was inspired by his middle school teacher, who said ‘if you don’t be a good Prime Minister, then be a good doctor’. He chose medicine and in 1989 went to Weifang Medical College, obtaining his bachelor’s degree in Medicine in 1994 and then to PUMC, where his mentor was Prof. Xian-Sheng Cheng, a famous expert in Cor Pulmonale. Having written his thesis on viral myocarditis and obtained a Medical Doctor’s degree in 1998, it was during his residency in FuWai Hospital—which is part of CAMS and includes the National Center for Cardiovascular Disease—where Prof. Jing’s interest in pulmonary hypertension (PH) developed. He specifically recalls a case of a 7-year-old girl referred to him with PH. To evaluate the therapeutic efficacy of diltiazem, he stayed at her bedside for 72 h to record hemodynamic data and found she responded to calcium channel blocker (CCB). That patient has since graduated from college, become a traffic police officer, and is now a volunteer educator for PH patients. ‘Back in 1998, no specific drug was available for patients with PH in China and many children and adults with congenital heart disease were diagnosed as having Eisenmenger syndrome because of PH’, he said. It was the plight of these patients that motivated his research into ‘this difficult area’. Post-doctoral training As a resident, Prof. Jing travelled throughout China to investigate PH patients and in 2002 found his first familial PH pedigree carrying BMPR2 mutation. In 2004, his publication of the mutation sites and clinical data of this family1 was also the first genetic study of PH in China. To extend his knowledge, he went to France and worked with Prof. Gérald Simonneau, who offered him post-doctoral training in his centre, and Prof. Marc Humbert at Hôpital Antoîne BéCLère, a well-known PH centre where he stayed for two years. In addition to learning the diagnosis and treatment of pulmonary vascular diseases, he also received training in clinical and basic research and met many international experts and subsequently conducted further collaborations with his French supervisors. His interest in French science, art, literature, and food was aroused, alongside his love of reading and travelling. After returning to Beijing, Prof. Jing was promoted to an associate professor of medicine and in 2007, his team published the first PH registry study in China,2 followed by the first Expert Consensus on Screening, Diagnosis and Treatment of Pulmonary Hypertension in China.3 Shanghai Pulmonary Hospital With the support of Wen Gao, President of Shanghai Pulmonary Hospital Affiliated to Tongji University, Prof. Jing established the Center of Cardio-Pulmonary Circulation in 2008, including an outpatient and inpatient clinic, catheter lab, echocardiography lab, and basic research team. His team also started balloon pulmonary angiography (BPA) in Shanghai Pulmonary Hospital and successfully treated chronic thromboembolic pulmonary hypertension (CTEPH) patients. Prof. Jing duly became a Professor of Medicine and Head of the Center for Cardio-Pulmonary Circulation, treating PH patients from across the country and transforming it into the largest pulmonary vascular disease centre in China. This also saw the establishment of a basic research laboratory, a biobank, clinical trials of novel drugs, and the start of interventional therapy on CTEPH patients. Since 2008 he has also organized the famous Long March academic conferences on pulmonary vascular disease. With few doctors focusing on PH research in China, Prof. Jing led the efficacy and safety study of almost all the listed PH targeted drugs in China. Young Investigator In 2009, his team was the first to prove that inhaled iloprost could be used to screen long-term responders to CCB, which solved the problem that acute pulmonary vasodilator test could not be carried out without inhaled nitric oxide (iNO) and Flolan.4 Further clinical trials in the treatment of PH were conducted and in 2010, the study of oral vardenafil for the treatment of PH was reported at the ESC conference where Prof. Jing won the Young Investigator Award that year. The following year, his team published the updated survival data of Chinese patients with PH5 showing the 3-year survival rate increased from 39% in 2007 to 75% in 2011. In addition to academic work, Prof. Jing trains specialists in pulmonary vascular disease from across China and many centres for pulmonary vascular diseases have been set up across the country. ‘We have formed a nationwide academic network to organize registry, genetics and other researches, such as multi-centre clinical trials for new drugs and medical devices’, said Prof. Jing. Hybrid treatment After seeing more patients with congenital heart diseases and CTEPH, Prof. Jing began to address how to conduct surgical-interventional hybrid treatment for complex CTEPH patients. A move back to FuWai—the largest cardiovascular scientific centre in China—in 2013 saw the development of treatment of CTEPH with cardiac surgeons carrying out pulmonary endarterectomy (PEA). With numbers of PEA increasing significantly in China, Prof. Jing has organized a team to refine the procedure of BPA. ‘Under the guidance of optical coherence tomography and fractional flow reserve, the efficacy of BPA was improved, and the complication rates decreased’, he said. ‘Many CTEPH patients who were not suitable for PEA or who had residual PH after PEA were cured by refined BPA. We also extended the application of refined BPA to pulmonary vascular occlusion lesion in pulmonary arteritis, with a high incidence in Asian population. This is a big breakthrough for the treatment of pulmonary arteritis’. Biobank In FuWai Hospital, he established a state-of-the-art pulmonary vascular scientific lab and built up one of the world’s largest biobanks of pulmonary vascular diseases. Using these samples, his team investigated the novel gene mutations involved in pulmonary vascular remodelling. By comprehensively exploring the aetiology of PH with the aid of genomics, metabolomics and proteomics, his team confirmed two new gene mutations related to PH, BMP9 and PTGIS, in 2017 and 2018, respectively.6,7 He also began to explore the mysteries ‘Eisenmenger syndrome’. Many were successfully treated for the condition, having undergone defects closure safely after cautious selection by the oxygen inhalation test. Head of Cardiology In January 2020, Prof. Jing was appointed Head of the Cardiology Department at PUMCH, CAMS, and PUMC, with a reputation for treating difficult, critical, and rare diseases, where his main interest remains on the relationship between congenital heart disease and PH, especially in the perspectives of genetics and developmental biology. Despite scientific research affected by the COVID-19 pandemic, Prof. Jing and his team continue to make progress in congenital heart disease associated PH, by repairing heart defects in selective patients after drug treatment. He also led a major new drug study, exploring the efficiency and safety of recombinant anti-human endothelin receptor A-humanized monoclonal antibody GMA301 for the treatment of PH, which is also the world's first antibody therapy in the area of PH. He said: ‘Looking back on the past 20 years, the life quality of patients with all types of PH in China have been dramatically improved, mainly thanks to research on new diagnosis and treatment methods. And we can never overlook the very important components: the establishment of a clinical cohort database and biobank, and the bedside-bench-bedside chain, which helps to support and accelerate more novel drug developments’. A new era Proud of the trust his patients place in him and the opportunity to use ‘the latest treatment methods to save their lives’, his message to young investigators is: ‘Twenty years ago, very few people in China paid attention to the field of PH, as it is a rare disease. Even now it’s still not a popular field of cardiology. But if you are interested in it and hold on in spite of the hard beginning, you will find a totally different world. Every field has a bright future’. With PUMCH marking its 100th anniversary, he looks forward to leading the long-established cardiology department into a new era (Figure 2). Figure 2 Open in new tabDownload slide The grand opening of Peking Union Medical College Hospital on September 16, 1921, and (right) the entire staff and retired professors of the Department of Cardiology in the old yard of the Peking Union Medical College Hospital. Figure 2 Open in new tabDownload slide The grand opening of Peking Union Medical College Hospital on September 16, 1921, and (right) the entire staff and retired professors of the Department of Cardiology in the old yard of the Peking Union Medical College Hospital. References 1 Zhicheng J , Lihe L, Zhiyan H, Xiansheng C, Yubao Z, Yuejin Y, Rutai H. Bone morphogenetic protein receptor-II mutation Arg491Trp causes malignant phenotype of familial primary pulmonary hypertension . Biochem Biophys Res Commun 2004 ; 315 : 1033 – 1038 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Jing Z-C , Xu X-Q, Han Z-Y, Wu Y, Deng K-W, Wang H, Wang Z-W, Cheng X-S, Xu B, Hu S-S, Hui R-T, Yang Y-J. Registry and survival study in Chinese patients with idiopathic and familial pulmonary arterial hypertension . Chest 2007 ; 132 : 373 – 379 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Chinese Society of Cardiology of Chinese Medical Association; Editorial Board of Chinese Journal of Cardiology . Experts consensus of diagnosis and treatment in pulmonary arterial hypertension . Zhonghua Xin Xue Guan Bing Za Zhi 2007 ; 35 : 979 – 987 . PubMed OpenURL Placeholder Text WorldCat 4 Jing Z-C , Jiang X, Han Z-Y, Xu X-Q, Wang Y, Wu Y, Lv H, Ma C-R, Yang Y-J, Pu J-L. Iloprost for pulmonary vasodilator testing in idiopathic pulmonary arterial hypertension . Eur Respir J 2009 ; 33 : 1354 – 1360 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Zhang R , Dai L-Z, Xie W-P, Yu Z-X, Wu B-X, Pan L, Yuan P, Jiang X, He J, Humbert M, Jing Z-C. Survival of Chinese patients with pulmonary arterial hypertension in the modern treatment era . Chest 2011 ; 140 : 301 – 309 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Wang X-J , Lian T-Y, Jiang X, Liu S-F, Li S-Q, Jiang R, Wu W-H, Ye J, Cheng C-Y, Du Y, Xu X-Q, Wu Y, Peng F-H, Sun K, Mao Y-M, Yu H, Liang C, Shyy JY-J, Zhang S-Y, Zhang X, Jing Z-C. Germline BMP9 mutation causes idiopathic pulmonary arterial hypertension . Eur Respir J 2019 ; 53 : 1801609 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Wang X-J , Xu X-Q, Sun K, Liu K-Q, Li S-Q, Jiang X, Zhao Q-H, Wang L, Peng F-H, Ye J, Wu Y, Jiang R, Zhang J, Huang W, Wei W-B, Yan Y, Li J-H, Liu Q-Q, Li S, Wang Y, Zhang S-Y, Zhang X, Jing Z-C. Association of rare PTGIS variants with susceptibility and pulmonary vascular response in patients with idiopathic pulmonary arterial hypertension . JAMA Cardiol 2020 ; 5 : 677 – 684 . Google Scholar Crossref Search ADS PubMed WorldCat Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Zhu, Jie Wei; Reed, Jennifer L; Van Spall, Harriette G C

doi: 10.1093/eurheartj/ehab846pmid: 34904147

The proportion of female athletes in competitive sporting events—including the World Championships and Olympic games—has increased to nearly half of all athletes, and competing athletes increasingly include those who are peripartum. While participation in sports is closely implicated in cardiovascular health and disease, females remain underrepresented in recreational and performance sports research. This underrepresentation is marked during pregnancy, a unique biological state with substantial hemodynamic changes that have implications on athletic performance and on any underlying cardiovascular conditions. The evidence to guide recreational and performance sports is derived mainly from research in males, which has limited generalizability in females. This is a call for researchers to include female participants, including consenting pregnant and lactating women, in sports physiology research and for guideline committees to include sex-specific and peripartum-specific cardiovascular recommendations for athletes. Underrepresentation of female athletes in sports research Females are under-enrolled in both recreational and performance sports research, and this parallels the underrepresentation of females in research across health and disease states.1 When female athletes are included, their sample sizes are frequently smaller than their male counterparts.2 Among 12 511 386 participants in 5261 manuscripts published in six sport and exercise science journals between 2014 and 2020, females accounted for 34% of the study population; in addition, only 6% of total publications were conducted exclusively on females. The underrepresentation female athletes in research translates to knowledge gaps about sex differences in cardiovascular physiology and sports performance,2,3 and there is limited knowledge to guide policy for training and participation in elite events. There is an urgent need for more females to be included in sports research and for more female-only research, which looks at the effects of sex-specific factors, such as the menstrual cycle, hormonal contraceptive use, pregnancy, and menopause on sports physiology, sports performance, and cardiovascular health.3,4 Biological factors unique to female athletes Findings of sports science research in males do not address the biological factors that are unique to females and impact their cardiovascular health.5 Females have unique health considerations, including different metabolism of medications, lower haemoglobin levels, and smaller cardiac volumes than males. Females are prone to iron deficiency anaemia related to menstruation and pregnancy. Hormonal fluctuations during different stages of the menstrual cycle may influence training and physical performance. For example, relaxin and oestrogen concentrations peak during the luteal phase of the menstrual cycle and are associated with an increased risk of injuries.5 Oestrogen and progesterone fluctuations during the menstrual cycle may also affect temperature regulation, central nervous system fatigue, basal metabolism, which all contribute to exercise performance and cardiovascular health. Aesthetic sports and caloric restriction may contribute to energy deficiency, with detrimental consequences on sports performance and cardiovascular health.5 Given the cardiovascular and cerebrovascular adaptations that occur during stages of pregnancy, recommendations for elite level exercise during the postpartum phase should be informed by evidence for maternal and foetal outcomes. Maternal cardiac output increases to ensure adequate perfusion to the uterus, placenta, and maternal organs.6 Maternal resting heart rate increases by, on average, 20 b.p.m. and stroke volume increases by ∼40% during gestation.6 Reversible chamber enlargement has also been observed, with atrial diameters expanding up to 40% secondary to the expanded blood volume of pregnancy.6 Blood pressure normally decreases during pregnancy due to progesterone, which promotes vascular smooth muscle relaxation and increased nitric oxide.6 Decreased cerebral blood flow has also been reported with no apparent changes to cerebral autoregulation during pregnancy.6 These pregnancy-related cardiovascular changes typically resolve after the first 4–12 postpartum weeks.6 Gaps in current recommendations Current guidelines indicate that it is safe for female athletes who were physically active before pregnancy to engage in recreational exercise during and after pregnancy, but recommendations regarding performance sports and knowledge regarding maternal and foetal outcomes are lacking.6 Inactivity during pregnancy has been associated with excessive weight gain, hypertensive disorders of pregnancy, and gestational diabetes—known risk factors for cardiovascular disease and foetal complications.7 The intensity and duration of physical activity during pregnancy can influence the degree of change in foetal cardiac autonomic control, but evidence is conflicting. In one study, females engaging in high intensity exercise were found to have foetuses with lower, more variable heart rate.7 However, studies on resistance training found that increased frequency, intensity, and duration of resistance training were associated with lower rates of foetal complications.7 The developing foetal cardiovascular system is thought to respond differently to various types of maternal exercise, but there are knowledge gaps pertaining to foetal outcomes that require further research.7 The impact of elite training on post-partum physiology and lactation remains unclear. Findings from an observational study with 16 post-partum participants showed that females who engaged in vigorous exercise for ≥45 min/day tended to produce higher milk volume and energy output.8 Another observational study in 41 top competitive athletes reported that elite female athletes can benefit substantially from training at high frequencies (i.e. 6-day exercise routine) during an uncomplicated pregnancy as this approach would facilitate a more rapid return to competitive sports in the post-partum period.9 However, current research is largely limited to observational studies with small sample sizes and further high-quality studies are needed. Strategies to close sex knowledge gaps in sports research There are several strategies to close the sex-specific knowledge gaps in sports training (Figure 1). First, investigating the cardiovascular physiology and health outcomes of female athletes requires representative inclusion of female athletes in the respective sport. Second, pregnant and lactating females should be included in sports research to close knowledge gaps and guide policy specific to this population. It is also essential to include those at different stages of pregnancy, as each is associated with distinct cardiovascular physiological changes. In addition, there is a need to change the ubiquitous male-directed branding and imagery in peer-reviewed scientific publications on sports physiology or performance sports in favour of gender-equal imagery. Figure 1 Open in new tabDownload slide Sex-specific knowledge gaps pertaining to sports performance, implications for cardiovascular health, and strategies to increase the inclusion of female athletes in sports research. CV, cardiovascular; SV, stroke volume; HR, heart rate; SVR, systemic vascular resistance; BP, blood pressure; BMI, body mass index. Figure 1 Open in new tabDownload slide Sex-specific knowledge gaps pertaining to sports performance, implications for cardiovascular health, and strategies to increase the inclusion of female athletes in sports research. CV, cardiovascular; SV, stroke volume; HR, heart rate; SVR, systemic vascular resistance; BP, blood pressure; BMI, body mass index. Strategies to increase the enrolment of females as research participants should include the recruitment, retention, and advancement of women sports researchers. Recruitment of female participants has been previously associated with trial leadership by women, who are largely underrepresented in leadership in sport and cardiovascular research.3,10 In fact, women accounted for ∼25% of first and <20% of senior authorship positions among >4800 randomized controlled trials published from January 2000 to September 2020 in high-impact sport sciences journals.5 The underrepresentation of women in research leadership positions may lead to lower prioritization of research questions specific to females and less emphasis on research representativeness. The critical gaps in knowledge pertaining to elite training in female athletes can only be closed by committing to transformative changes in the way research is conducted. The systematic exclusion of pregnant and post-partum athletes, and the underrepresentation of females in general, must no longer be considered acceptable and efforts must be made at multiple levels to ensure that research participants are representative of the population to which findings apply. Conflict of interest: The authors hereby declare no conflicts of interest. Data availability There are no new data associated with this article. References 1 Van Spall HGC. Exclusion of pregnant and lactating women from COVID-19 vaccine trials: a missed opportunity . Eur Heart J 2021 ; 42 : 2724 – 2726 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Michos ED , Van Spall HGC. Increasing representation and diversity in cardiovascular clinical trial populations . Nat Rev Cardiol 2021 ; 18 : 537 – 538 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Whitelaw S , Sullivan K, Eliya Y et al. Trial characteristics associated with under-enrolment of females in randomized controlled trials of heart failure with reduced ejection fraction: a systematic review . Eur J Heart Fail 2021 ; 23 : 15 – 24 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Cowley ES , Olenick AA, McNulty KL, Ross EZ. “Invisible sportswomen”: the sex data gap in sport and exercise science research . Women Sport Phys Act J 2021 ; 29 : 146 – 151 . Google Scholar Crossref Search ADS WorldCat 5 Martínez-Rosales E , Hernández-Martínez A, Sola-Rodríguez S, Esteban-Cornejo I, Soriano-Maldonado A. Representation of women in sport sciences research, publications, and editorial leadership positions: are we moving forward? J Sci Med Sport 2021 ; 24 : 1093 – 1097 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Sanghavi M , Rutherford JD. Cardiovascular physiology of pregnancy . Circulation 2014 ; 130 : 1003 – 1008 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Beilock SL , Feltz DL, Pivarnik JM. Training patterns of athletes during pregnancy and postpartum . Res Q Exerc Sport 2001 ; 72 : 39 – 46 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Lovelady CA , Lonnerdal B, Dewey KG. Lactation performance of exercising women . Am J Clin Nutr 1990 ; 52 : 103 – 109 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Kardel KR. Effects of intense training during and after pregnancy in top-level athletes . Scand J Med Sci Sports 2005 ; 15 : 79 – 86 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Van Spall HGC , Lala A, Deering TF et al. ; Global CardioVascular Clinical Trialists (CVCT) Forum and Women As One Scientific Expert Panel . Ending gender inequality in cardiovascular clinical trial leadership: JACC review topic of the week . J Am Coll Cardiol 2021 ; 77 : 2960 – 2972 . Google Scholar Crossref Search ADS PubMed WorldCat Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Reid, Christopher M; Patel, Anushka; Nicholls, Stephen J; Briffa, Tom

doi: 10.1093/eurheartj/ehab753pmid: 34791159

Over the past decades, Australian and New Zealand cardiovascular researchers have participated and led cardiovascular clinical trials which have had a major influence on clinical practice. In the acute care setting, these included the ISIS and GUSTO trials where, of the 41 021 patients randomized in the GUSTO-1 study, 2287 were from Australian centres and 666 from New Zealand.1,2 In the area of cardiovascular risk factor management, Australian clinical trialists designed and conducted a number of pivotal trials; the Australian National Blood Pressure (ANBP) Study,3 the LIPID trial,4 and ANBP2.5 The ANBP trial was key in establishing the role of treatment of mild hypertension in the early 1980s. The LIPID trial randomized 9014 patients at 87 participating sites and set a benchmark for future research: only one patient was lost to follow-up, and ANBP2 included 6083 participants recruited nationally from primary care. Despite these successes of the past, cardiovascular trials in Australia have become more challenging and recruitment of patients decreasing in major tertiary centres who previously led trial recruitment. For industry sponsored and investigator initiated international cardiovascular clinical trials, major recruitment sites have shifted from Australasia, North America, and Western Europe to Eastern Europe, South America, and Asian countries including China.6 Current barriers to recruitment for hospital based cardiovascular trials are unclear but may be related to a decline in outpatient clinics, difficulties in ensuring long-term follow-up within the public health care system, competing demands on the time of all clinicians, a lack of research training for younger cardiologists and a consequent waning of interest in research. Some hospital administrators have a negative attitude to research, and there are cost pressures within all sectors of health care. In an attempt to address this problem, the Cardiac Society of Australia and New Zealand (CSANZ) Clinical Trials Council held a meeting in August 2016 which Focused on barriers to establishing a collaborative network for the conduct of cardiovascular trials across the spectrum of clinical craft groups. An additional key driver for the meeting was an announcement from the newly established Australian Medical Research Future Fund (MRFF) that included formal clinical trial networks (CTN) among its initial priorities.7 The fact that no formalized cardiovascular CTN existed despite more than 40 other discipline-specific CTNs in Australia put cardiovascular trials at a disadvantage. Established CTNs are increasingly securing larger absolute numbers of grants and amounts of competitive research funding for both people and projects.8 In 2015, for 34 CTNs in Australia, the estimated median total research funding generated over the past 5 years per network was between $2.5 and $10 million, but ranged from $10 to $25 million for four networks, $25–50 million for one network, and more than $50 million for five networks.8 The CSANZ meeting unanimously supported the idea of establishing a cardiovascular trials network to maximize opportunities for cardiovascular trials in Australia and New Zealand. In February 2017, a subsequent workshop was held in Melbourne to discuss the formalization of the Australian and New Zealand Alliance for Cardiovascular Trials (ANZACT) Network. Sessions on the need for the CTN, network type (Facilitating or Coordinating), governance, role of the CTN and prospective partners were conducted. More than 100 people attended from throughout Australia and New Zealand, reflecting a high level of interest in the concept and support from cardiovascular clinical researchers. The workshop was held in collaboration with the Australian Clinical Trials Alliance (ACTA). Potential benefits arising from ANZACT included more than just the identification of a group of investigators to participate in the recruitment for individual cardiovascular trials. The network can support in the trials processes of multi-centre ethics applications, establishment of data safety and monitoring and identification of support centres for investigators in need of clinical trial management expertise including database development and design. Within the network, greater dialogue between active researchers could improve their capacity to formulate research strategies and optimize the use of data accumulated within each study in addition to providing a forum for attracting and nuturing new and early career researchers. Importantly, a network would assist in establishing and maintaining the skills and infrastructure which are essential for clinical trials, but which sometimes dissipate once a major study has been completed. In communicating the benefits to government and other funders, the focus should be not on the research itself, but on the opportunities to improve outcomes for individual patients the effectiveness and cost-effectiveness of cardiovascular health services. ANZACT Network impact to date ANZACT now has over 260 members across Australia and New Zealand and has engagement with all major clinical trial coordinating centres who focus on cardiovascular trials.9 ANZACT has been established as a trial facilitating network Focused on capacity building and aims to promote trials without being directly involved in their conduct. Endorsement of a trial is the key activity of several successful networks, including ANZACT, which then invests its reputation in the success of the project. Endorsement may involve vigorous but positive discussion of the rationale and methodology, and the process of peer review strengthens the trial’s design and the likelihood of a success. Endorsement then facilitates the activities of the coordinating centre, particularly in encouraging recruitment by individual sites. ANZACT has held five peer-review workshops following establishment as a formalized network and the focus has been on both concept development for new trials and critical review of trials being submitted for funding applications. The Scientific Review Committee is chaired by Professor Stephen Nicholls. Ms. Karen Carey chairs the Consumer review Committee providing critical consumer co-design input to trials in the development stage. To date, ANZACT has reviewed sixteen trials where the funding outcomes are known and five of these trials were successfully funded through the NHMRC Clinical Trials or the MRFF International Clinical Trials Scheme. The ∼20% success rate is well ahead of the overall success rates of these schemes which is currently ∼5–7%.10 ANZACTs vision is for Australia and New Zealand to lead and participate in the development and conduct of cardiovascular trials of the highest domestic and global relevance and to achieve this through utilizing established clinical trial facilities and state and national cardiovascular registries. Our strategic plan over the next 4 years (Figures 1and2) remains focused on supporting Australian and New Zealand academic cardiologists and cardiovascular trialists in achieving this vision. Figure 1 Open in new tabDownload slide ANZACT vision, mission and guiding principles underlying our strategic plan for 2020–2024 (available at https://anzact.org, 27 October 2021). Figure 1 Open in new tabDownload slide ANZACT vision, mission and guiding principles underlying our strategic plan for 2020–2024 (available at https://anzact.org, 27 October 2021). Figure 2 Open in new tabDownload slide ANZACT Scientific Committee meetings remained fully engaged on line during the long COVID19-related shutdowns across Australia and New Zealand in 2020. Figure 2 Open in new tabDownload slide ANZACT Scientific Committee meetings remained fully engaged on line during the long COVID19-related shutdowns across Australia and New Zealand in 2020. Acknowledgements The ANZACT Executive Committee members are as follows: Prof. Chris Reid—Chair (WA), Prof. Stephen Nicholls—Chair Scientific Committee (VIC), Ms. Karen Carey—Chair Community Advisory Group (WA), Prof. Anushka Patel (NSW), Prof. Derek Chew (SA), Prof. Markus Schlaich (WA), Prof. Ralph Stewart (NZ), Prof. Tom Briffa (WA), Dr. Emily Atkins—Early Career Researcher (NSW), Ms. Angela Brennan—Registry Liaison (VIC), and Ms. Julia Fallon-Ferguson—Executive Officer (WA). Funding The establishment of the ANZACT Clinical Trials Network was supported by the National Health and Medical Research Council Centre of Research Excellence in Cardiovascular Outcomes Improvement (GNT111170). Conflict of interest: none declared. References 1 Lee KL , Woodlief LH, Topol EJ et al. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction . Circulation 1995 ; 91 : 1659 – 1668 . Google Scholar Crossref Search ADS PubMed WorldCat 2 ISIS-2 Collaborative Group . Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2 . J Am Coll Cardiol 1988 ; 12 : A3 – A13 . Crossref Search ADS WorldCat 3 Management Committee . Australian therapeutics trials in mild hypertension . The Lancet 1980 ; 1 : 1261 – 1267 . OpenURL Placeholder Text WorldCat 4 Lipid Study Group . Long-term effectiveness and safety of pravastatin in 9014 patients with coronary heart disease and average cholesterol concentrations: the LIPID trial follow-up . The Lancet 2002 ; 359 : 1379 – 1387 . Crossref Search ADS WorldCat 5 Wing LMH , Reid CM, Ryan P et al. ; Second Australian National Blood Pressure Study Group . A comparison of outcomes with angiotensin-converting–enzyme inhibitors and diuretics for hypertension in the elderly . N Engl J Med 2003 ; 348 : 583 – 592 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Drain PK , Robine M, Holmes KK, Bassett IV. Global migration of clinical trials . Nat Rev Drug Discov 2014 ; 13 : 166 – 167 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Medical Research Future Fund . Australian medical research and innovation priorities 2016–2018. http://health.gov.au/internet/main/publishing.nsf/Content/mrff/$FILE/Australian%20Medical%20Research%20and%20Innovation%20Priorities%202016.pdf2015. 8 Australian Clinical Trials Alliance . Report on the Activities & Achievements of Clinical Trials Networks in Australia 2004-2014. Melbourne: ACTA; 2015 . 9 ANZACT Steering Committee. The ANZACT Network , 2017 . https://anzactorg/. 10 National Health and Medical Research Council. Clinical Trials and Cohort Studies Grants 2019 Outcomes Factsheet, 2020 . https://wwwnhmrcgovau/outcomes#download. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Jang, Shih-Jung; Chen, Ying-Hwa; Shen, Ta-Chung

doi: 10.1093/eurheartj/ehab824pmid: 34864965

An 89-year-old male with symptomatic severe aortic stenosis underwent transfemoral transcatheter aortic valve implantation. The pre-procedural computed tomography showed horizontal aorta along with heavy calcification of both right and non-coronary cusps (Panels A and B). We attempted to deploy a 29-mm Evolut R utilizing cusp overlap technique in the beginning, but the prosthesis tended to migrate upward before reaching the point of no recapture even with controlled pacing. After the prosthesis had been fully recaptured up to three times, we removed the system and proceeded with a second valve. Using conventional implantation technique to deploy the second valve, we achieved an implant depth of 2 mm and mild paravalvular leak (Panel C and Supplementary material online, Video S1). Unexpectedly, a 9.8-mm aortic valve debris (Panels D–F) was discovered between inflow struts and nose cone on the retrieved first valve (Supplementary material online, Video S2). We also noticed infolding of the retrieved first valve, which may be associated with multiple recaptures in the presence of significant annular calcification (Panel G). The patient was discharged uneventfully 4 days later. This case illustrates that cusp overlap technique might not work for patients with horizontal aorta. Because the prosthesis barely descended from mid-pigtail level into left ventricle by gravity, the first implanter had to constantly apply tension on the delivery system. Inflow struts of partially unsheathed prosthesis with a gap between inflow struts and nose cone may scrape and dislocate aortic valve debris/calcium deposits both during re-advancing a partially recaptured prosthesis or during valve positioning (Panel H). Panels A and B: Computed tomography demonstrating horizontal aorta as well as heavy calcification of both right and non-coronary cusps; Panel C and Supplementary material online, Video S1: final result showing a second valve deployed with conventional implantation technique; Panels D–E and Supplementary material online, Video S2: revealing a large aortic valve debris between inflow struts and nose cone on the retrieved first valve; Panel F: histopathology of valve tissue with calcifications; Panel G: infolding of the retrieved first valve; and Panel H: the schematic diagram illustrating aortic valve debris/calcium deposits is scraped and dislocated during valve positioning. AV, aortic valve; C, calcium deposits on aortic valve. Supplementary material is available at European Heart Journal online. Funding: The authors report no specific funding related to this article. Conflict of interest: Y.-H.C. is a proctor for the Medtronic CoreValve and Evolut R. Other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Data availability: The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials. Open in new tabDownload slide Open in new tabDownload slide Author notes † Shih-Jung Jang, Ying-Hwa Chen contributed equally to this work. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Bedeir, Kareem; Robichaux, Robert P; Gleason, Thomas G

doi: 10.1093/eurheartj/ehab859pmid: 34910108

A 38-year-old male with a mechanical aortic valve implanted 15 years ago for rheumatic disease presented to the hospital with sudden cardiopulmonary collapse. Upon arrival, he was in shock on high-dose pressors, intubated and mechanically ventilated. Chest radiograph revealed marked pulmonary oedema, and known mechanical valve was not well visualized on the film. A transthoracic echocardiogram showed severe turbulence across the left ventricular outflow tract, severe aortic regurgitation, and the known mechanical valve could not be visualized. A tomogram showed the mechanical valve in the distal aortic arch (Panels A and B). The patient was immediately taken to the operating room. Emergency re-operative sternotomy was done expeditiously. Cardiopulmonary bypass (CPB) was initiated and the patient was cooled to allow for circulatory arrest. With an arrested circulation, the aortic arch was opened via an anterior aortotomy, the embolized mechanical valve explanted, and debris removed (Panels C and D). The circulation was resumed and patient rewarmed. The aortic annulus showed extensive and circumferential liquefactive necrosis. Multiple pericardial patches were used to reconstruct the annulus and root, and a new mechanical valve was reimplanted. The patient was liberated from CPB in the standard manner. The patient was discharged to home with full functional capacity on postoperative Day 16. Embolization of a whole surgical valve is exceedingly rare. Over the 60 years of valve replacement surgery, only two patients survived distal whole valve embolization. Management is emergent surgery, with approach tailored to the haemodynamics and site of embolization. Panels A and B: computed tomography scan showing the embolized mechanical valve in the distal aortic arch. Panel C shows the explanted valve en bloc with eroded native annulus. Panel D shows the mechanical valve being explanted from the aortic arch incision under deep hypothermic circulatory arrest. Funding: the authors report no specific funding related to this article. Conflict of interest: The authors have submitted their declaration which can be found in the article Supplementary Material online. Open in new tabDownload slide Open in new tabDownload slide Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Donato, Federica; Boskoski, Ivo; Tinelli, Giovanni; Tshomba, Yamume

doi: 10.1093/eurheartj/ehab860pmid: 34904148

A 64-year-old man with history of pulmonary embolism placed about 30 years back an inferior vena cava (IVC) filter. Computed tomography (CT) scan incidentally revealed the penetration of the IVC filter struts through the wall of the IVC and duodenum (Panel A). Esophagogastroduodenoscopy (EGD) showed two metallic foreign bodies protruding from the second portion of the duodenal wall (Panel B). The patient was asymptomatic. After multi-disciplinary discussion, an exploratory laparotomy was planned in order to remove the filter and to repair IVC and duodenum. Surgical exposure was performed through a xipho-pubic laparotomy. Although it was difficult to mobilize the duodenum due to adhesion resulting from inflammation of the surrounding soft tissues, the duodenum was reflexed with the Kocher manoeuver. Dissection of retroperitoneum revealed the IVC filter struts perforating the vein wall in multiple directions, the duodenal serosa, and the head of the pancreas (Panel C). Parts of filter protruding into the duodenum and the pancreas was extracted and dissected with a wire cutter. After clamping the IVC, the filter was removed through a cavotomy and the IVC incision was closed using a patch in bovine pericardium (Panel D). To prevent duodenal bleeding or perforation, the duodenal penetration site was reinforced using Vycril 3-0 suture. The patient did not develop any postoperative complications and was discharged on VII postoperative day. Open in new tabDownload slide Open in new tabDownload slide Panel A: The preoperative CT. Panel B: EGD. Panel C: Intraoperative details of IVC struts perforating vein wall. Panel D: Bovine pericardial patch for IVC reconstruction. Funding: The authors report no specific funding related to this article. Conflict of interest: The authors have submitted their declaration which can be found in the article Supplementary Material online. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)