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1. Treatment of Primary Aldosteronism and Reversal of Renin Suppression Improves Left Ventricular Systolic Function

Author

Troy H. Puar, Chin Kai Cheong, Roger S.Y. Foo, Seyed Ehsan Saffari, Tian Ming Tu, Min Ru Chee, Meifen Zhang, Keng Sin Ng, Kang Min Wong, Andrew Wong, Foo Cheong Ng, Tar Choon Aw, Joan Khoo, Linsey Gani, Thomas King, Wann Jia Loh, Shui Boon Soh, Vanessa Au, Tunn Lin Tay, Eberta Tan, Lily Mae, Jielin Yew, Yen Kheng Tan, Khim Leng Tong, Sheldon Lee, and Siang Chew Chai

Subjects
hyperaldosteronism, adrenalectomy, secondary hypertension, adrenal vein sampling (AVS), myocardial strain analysis, ejection fraction (EF), Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

IntroductionPrimary aldosteronism (PA) is associated with increased risk of cardiovascular events. However, treatment of PA has not been shown to improve left ventricular (LV) systolic function using the conventional assessment with LV ejection fraction (LVEF). We aim to use speckle-tracking echocardiography to assess for improvement in subclinical systolic function after treatment of PA.MethodsWe prospectively recruited 57 patients with PA, who underwent 24-h ambulatory blood pressure (BP) measurements and echocardiography, including global longitudinal strain (GLS) assessment of left ventricle, at baseline and 12 months post-treatment.ResultsAt baseline, GLS was low in 14 of 50 (28.0%) patients. On multivariable analysis, GLS was associated with diastolic BP (P = 0.038) and glomerular filtration rate (P = 0.026). GLS improved post-surgery by −2.3, 95% CI: −3.9 to −0.6, P = 0.010, and post-medications by −1.3, 95% CI: −2.6 to 0.03, P = 0.089, whereas there were no changes in LVEF in either group. Improvement in GLS was independently correlated with baseline GLS (P < 0.001) and increase in plasma renin activity (P = 0.007). Patients with post-treatment plasma renin activity ≥1 ng/ml/h had improvements in GLS (P = 0.0019), whereas patients with persistently suppressed renin had no improvement. Post-adrenalectomy, there were also improvements in LV mass index (P = 0.012), left atrial volume index (P = 0.002), and mitral E/e’ (P = 0.006), whereas it was not statistically significant in patients treated with medications.ConclusionTreatment of hyperaldosteronism is effective in improving subclinical LV systolic dysfunction. Elevation of renin levels after treatment, which reflects adequate reversal of sodium overload state, is associated with better systolic function after treatment.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier: NCT03174847.

Published
2022
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2. Modified CRISPR/Cas9 mediated generation of two MKK7 knockout human embryonic stem cell lines

Author

C.H. Cole Sims, Matias I. Autio, Adriana Buskin, Christine Cheung, Rakesh Heer, Roger S.Y. Foo, and Xin Wang

Subjects
Biology (General), QH301-705.5
Abstract

Two cell lines were generated by CRISPR/Cas9 mediated knockout of MKK7 (MAP2K7) by removal of exon 1 or exons 4 through 7. These knockouts were confirmed at the transcript and protein levels. These hESCs are pluripotent and maintain tri-lineage differentiation capacity. These cell lines are a useful resource for studying MKK7 function in humans.

Published
2021
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3. Cardiac remodelling - Part 2

Author

Alberto Aimo, Giuseppe Vergaro, Arantxa González, Andrea Barison, Josep Lupón, Victoria Delgado, A Mark Richards, Rudolf A. de Boer, Thomas Thum, Henrike Arfsten, Martin Hülsmann, Inês Falcao‐Pires, Javier Díez, Roger S.Y. Foo, Mark Yan Yee Chan, Chukwuemeka G. Anene‐Nzelu, Magdy Abdelhamid, Stamatis Adamopoulos, Stefan D. Anker, Yuri Belenkov, Tuvia Ben Gal, Alain Cohen‐Solal, Michael Böhm, Ovidiu Chioncel, Ewa A. Jankowska, Finn Gustafsson, Loreena Hill, Tiny Jaarsma, James L. Januzzi, Pardeep Jhund, Yuri Lopatin, Lars H. Lund, Marco Metra, Davor Milicic, Brenda Moura, Christian Mueller, Wilfried Mullens, Julio Núñez, Massimo F. Piepoli, Amina Rakisheva, Arsen D. Ristić, Patrick Rossignol, Gianluigi Savarese, Carlo G. Tocchetti, Sophie van Linthout, Maurizio Volterrani, Petar Seferovic, Giuseppe Rosano, Andrew J.S. Coats, Michele Emdin, Antoni Bayes‐Genis, and Publica

Subjects
Ejection fraction, CONVERTING-ENZYME-INHIBITORS, Left, Cardiology, Heart failure, Ventricular Function, Left, Imaging, VENTRICULAR EJECTION FRACTION, PROGNOSTIC-SIGNIFICANCE, Humans, Ventricular Function, TROPONIN-T, Ventricular Remodeling, Biomarkers, Predictors, Remodelling, Therapies, Stroke Volume, Heart Failure, LATE GADOLINIUM ENHANCEMENT, RESYNCHRONIZATION THERAPY, DILATED CARDIOMYOPATHY INSIGHTS, MYOCARDIAL-INFARCTION, CARDIOVASCULAR MAGNETIC-RESONANCE, AORTIC-VALVE-REPLACEMENT, Cardiology and Cardiovascular Medicine
Abstract

In patients with heart failure, the beneficial effects of drug and device therapies counteract to some extent ongoing cardiac damage. According to the net balance between these two factors, cardiac geometry and function may improve (reverse remodelling, RR) and even completely normalize (remission), or vice versa progressively deteriorate (adverse remodelling, AR). RR or remission predict a better prognosis, while AR has been associated with worsening clinical status and outcomes. The remodelling process ultimately involves all cardiac chambers, but has been traditionally evaluated in terms of left ventricular volumes and ejection fraction. This is the second part of a review paper by the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology dedicated to ventricular remodelling. This document examines the proposed criteria to diagnose RR and AR, their prevalence and prognostic value, and the variables predicting remodelling in patients managed according to current guidelines. Much attention will be devoted to RR in patients with heart failure with reduced ejection fraction because most studies on cardiac remodelling focused on this setting. © 2022 European Society of Cardiology.

Published
2022

4. Cardiac remodelling - Part 1: From cells and tissues to circulating biomarkers. A review from the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology

Author

Arantxa González, A. Mark Richards, Rudolf A. de Boer, Thomas Thum, Henrike Arfsten, Martin Hülsmann, Inês Falcao‐Pires, Javier Díez, Roger S.Y. Foo, Mark Y. Chan, Alberto Aimo, Chukwuemeka G. Anene‐Nzelu, Magdy Abdelhamid, Stamatis Adamopoulos, Stefan D. Anker, Yuri Belenkov, Tuvia Ben Gal, Alain Cohen‐Solal, Michael Böhm, Ovidiu Chioncel, Victoria Delgado, Michele Emdin, Ewa A. Jankowska, Finn Gustafsson, Loreena Hill, Tiny Jaarsma, James L. Januzzi, Pardeep S. Jhund, Yuri Lopatin, Lars H. Lund, Marco Metra, Davor Milicic, Brenda Moura, Christian Mueller, Wilfried Mullens, Julio Núñez, Massimo F. Piepoli, Amina Rakisheva, Arsen D. Ristić, Patrick Rossignol, Gianluigi Savarese, Carlo G. Tocchetti, Sophie Van Linthout, Maurizio Volterrani, Petar Seferovic, Giuseppe Rosano, Andrew J.S. Coats, Antoni Bayés‐Genís, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Navarra Institute for Health Research / Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA)-Universidad de Navarra [Pamplona] (UNAV)-Clínica Universidad de Navarra [Pamplona], Instituto de Salud Carlos III [Madrid] (ISC), Yong Loo Lin School of Medicine [Singapore], National University of Singapore (NUS), University of Otago [Dunedin, Nouvelle-Zélande], University Medical Center Groningen [Groningen] (UMCG), Hannover Medical School [Hannover] (MHH), Fraunhofer Institute for Toxicology and Experimental Medicine (Fraunhofer ITEM), Fraunhofer (Fraunhofer-Gesellschaft), Medizinische Universität Wien = Medical University of Vienna, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, Departments of Cardiology and Cardiac Surgery, and Nephrology, Clínica Universidad de Navarra, Clínica Universidad de Navarra [Pamplona], Scuola Universitaria Superiore Sant'Anna [Pisa] (SSSUP), Fondazione Toscana Gabriele Monasterio, Montreal Heart Institute - Institut de Cardiologie de Montréal, Cairo University - Faculty of Medicine, Onassis Cardiac Surgery Center [Athens] (OCSC), Charité Campus Virchow-Klinikum (CVK), Berlin-Brandenburg Center for Regenerative Medicine [Berlin, Germany] (BCRT), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Université d'État Lomonossov de Moscou = Lomonosov Moscow State University (MSU), Cardiology Department, Rabin Medical Center, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Saarland University Hospital (UKS), Emergency Institute for Cardiovascular Diseases 'Prof. Dr. C.C. Iliescu' [Bucharest, Romania], Leiden University Medical Center (LUMC), Wrocław Medical University, Hôpital national = Rigshospitalet [Copenhagen, Denmark] (HNC), Queen's University [Belfast] (QUB), Linköping University (LIU), Massachusetts General Hospital [Boston], Baim Institute for Clinical Research Boston MA, British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Volgograd State Medical University [Russian Federation] (VSMU), Karolinska University Hospital [Stockholm], Karolinska Institutet [Stockholm], Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia [Brescia], Università degli Studi di Brescia = University of Brescia (UniBs), University of Zagreb, Cardiology Department, Porto Armed Forces Hospital, University Hospital Basel [Basel], Ziekenhuis Oost-Limburg (ZOL), Universitat de València (UV), Hospital Clínico Universitario de Valencia, Cardiology Division, Castelsangiovanni Hospital, Scientific Research Institute of Cardiology and Internal Medicine [Almaty, Kazakhstan], University Clinical Centre of Serbia, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), University of Naples Federico II = Università degli studi di Napoli Federico II, IRCCS Ospedale San Raffaele [Milan, Italy], Serbian Academy of Sciences and Arts (SASA), University of Belgrade [Belgrade], St George’s University Hospitals, University of Warwick [Coventry], Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain] (GTPUH), Universitat Autònoma de Barcelona (UAB), This work was supported by grants from the Spanish Ministry of Science, Innovation and Universities Institute of Health Carlos III (ISCIII) (PI18/01469 and PI21/00946 to A.G., CB16/11/00403 to A.B.-G and CB16/11/00483 to J.D. projects co-funded by the European Regional Development Funds), the European Commission (H2020 CRUCIAL project 2019–848109-2 to A.G.), the European Research Council (ERC CoG 818715 to R.A.d.B., ERC-PoC Megfib to T.T.), the National Medical Research Council of Singapore (NMRC, NMRC/STaR/0022/2014 to A.M.R. and MOH-000280 to M.Y.C.), the Health Research Council of New Zealand (02/152, 08/070, 11/1070), National Heart Foundation of New Zealand, New Zealand Lotteries Grant Board, Foundation for Research, Science and Technology and the Christchurch Heart Institute Trust to A.M.R., the Netherlands Heart Foundation (2017-21, 2017-11, 2018-30, 2020B005) to R.A.d.B., the leDucq Foundation (Cure-PLaN) to R.A.d.B., the Deutsche Forschungsgemeinschaft (KFO311 and TRR267 to T.T., TTR 219 to M.B., and TRR 1470 to S.V.L.), the Karolinska Institutet, the Swedish Research Council (523–2014-2336), the Swedish Heart Lung Foundation (20150557, 20190310), and the Stockholm County Council (20170112, 20190525) to L.H.L., European Project, BOZEC, Erwan, H2020 CRUCIAL project 2019–848109-2 - INCOMING, and Universiteit Leiden

Subjects
Heart Failure, Tissue, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Biomarkers, Cells, Remodeling, Endothelial Cells, Humans, Ventricular Remodeling, Cardiology, Cardiology and Cardiovascular Medicine, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract

International audience; Cardiac remodelling refers to changes in left ventricular structure and function over time, with a progressive deterioration that may lead to heart failure (HF) development (adverse remodelling) or vice versa a recovery (reverse remodelling) in response to HF treatment. Adverse remodelling predicts a worse outcome, whilst reverse remodelling predicts a better prognosis. The geometry, systolic and diastolic function and electric activity of the left ventricle are affected, as well as the left atrium and on the long term even right heart chambers. At a cellular and molecular level, remodelling involves all components of cardiac tissue: cardiomyocytes, fibroblasts, endothelial cells and leucocytes. The molecular, cellular and histological signatures of remodelling may differ according to the cause and severity of cardiac damage, and clearly to the global trend toward worsening or recovery. These processes cannot be routinely evaluated through endomyocardial biopsies, but may be reflected by circulating levels of several biomarkers. Different classes of biomarkers (e.g. proteins, non-coding RNAs, metabolites and/or epigenetic modifications) and several biomarkers of each class might inform on some aspects on HF development, progression and long-term outcomes, but most have failed to enter clinical practice. This may be due to the biological complexity of remodelling, so that no single biomarker could provide great insight on remodelling when assessed alone. Another possible reason is a still incomplete understanding of the role of biomarkers in the pathophysiology of cardiac remodelling. Such role will be investigated in the first part of this review paper on biomarkers of cardiac remodelling.

Published
2022

5. Large-Scale Whole-Genome Sequencing of Three Diverse Asian Populations in Singapore

Author

Degang Wu, Jinzhuang Dou, Xiaoran Chai, Claire Bellis, Andreas Wilm, Chih Chuan Shih, Wendy Wei Jia Soon, Nicolas Bertin, Clarabelle Bitong Lin, Chiea Chuen Khor, Michael DeGiorgio, Shanshan Cheng, Li Bao, Neerja Karnani, William Ying Khee Hwang, Sonia Davila, Patrick Tan, Asim Shabbir, Angela Moh, Eng-King Tan, Jia Nee Foo, Liuh Ling Goh, Khai Pang Leong, Roger S.Y. Foo, Carolyn Su Ping Lam, Arthur Mark Richards, Ching-Yu Cheng, Tin Aung, Tien Yin Wong, Huck Hui Ng, Jianjun Liu, Chaolong Wang, Matthew Andrew Ackers-Johnson, Edita Aliwarga, Kenneth Hon Kim Ban, Denis Bertrand, John C. Chambers, Dana Leng Hui Chan, Cheryl Xue Li Chan, Miao Li Chee, Miao Ling Chee, Pauline Chen, Yunxin Chen, Elaine Guo Yan Chew, Wen Jie Chew, Lynn Hui Yun Chiam, Jenny Pek Ching Chong, Ivan Chua, Stuart A. Cook, Wei Dai, Rajkumar Dorajoo, Chuan-Sheng Foo, Rick Siow Mong Goh, Axel M. Hillmer, Ishak D. Irwan, Fazlur Jaufeerally, Asif Javed, Justin Jeyakani, John Tat Hung Koh, Jia Yu Koh, Pavitra Krishnaswamy, Jyn Ling Kuan, Neelam Kumari, Ai Shan Lee, Seow Eng Lee, Sheldon Lee, Yen Ling Lee, See Ting Leong, Zheng Li, Peter Yiqing Li, Jun Xian Liew, Oi Wah Liew, Su Chi Lim, Weng Khong Lim, Chia Wei Lim, Tingsen Benson Lim, Choon Kiat Lim, Seet Yoong Loh, Au Wing Lok, Calvin W.L. Chin, Shivani Majithia, Sebastian Maurer-Stroh, Wee Yang Meah, Shi Qi Mok, Niranjan Nargarajan, Pauline Ng, Sarah B. Ng, Zhenyuan Ng, Jessica Yan Xia Ng, Ebonne Ng, Shi Ling Ng, Simon Nusinovici, Chin Thing Ong, Bangfen Pan, Vincent Pedergnana, Stanley Poh, Shyam Prabhakar, Kumar M. Prakash, Ivy Quek, Charumathi Sabanayagam, Wei Qiang See, Yee Yen Sia, Xueling Sim, Wey Cheng Sim, Jimmy So, Dinna K.N. Soon, E. Shyong Tai, Nicholas Y. Tan, Louis C.S. Tan, Hong Chang Tan, Wilson Lek Wen Tan, Moses Tandiono, Amanda Tay, Sahil Thakur, Yih Chung Tham, Zenia Tiang, Grace Li-Xian Toh, Pi Kuang Tsai, Lavanya Veeravalli, Chandra S. Verma, Ling Wang, Min Rui Wang, Wing-Cheong Wong, Zhicheng Xie, Khung Keong Yeo, Liang Zhang, Weiwei Zhai, Yi Zhao, Cardiovascular Centre (CVC), Lee Kong Chian School of Medicine (LKCMedicine), and School of Biological Sciences

Subjects
Male, medicine.medical_specialty, Demographic history, Population, Genome-wide association study, HAPLOTYPE, Biology, VARIANTS, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, ANCESTRY ESTIMATION, 03 medical and health sciences, 0302 clinical medicine, Whole-genome Sequencing, Asian People, HISTORY, medicine, Humans, WIDE ASSOCIATION, Medicine [Science], Selection, Genetic, education, ADAPTATION, 030304 developmental biology, Whole genome sequencing, Singapore, 0303 health sciences, Genetic diversity, education.field_of_study, Whole Genome Sequencing, Asian Populations, Genome, Human, Malaysia, Human genetics, GENOTYPE, MODEL, Genetics, Population, Evolutionary biology, Medical genetics, Female, HEALTH, HUMAN-EVOLUTION, 030217 neurology & neurosurgery, Imputation (genetics)
Abstract

Underrepresentation of Asian genomes has hindered population and medical genetics research on Asians, leading to population disparities in precision medicine. By whole-genome sequencing of 4,810 Singapore Chinese, Malays, and Indians, we found 98.3 million SNPs and small insertions or deletions, over half of which are novel. Population structure analysis demonstrated great representation of Asian genetic diversity by three ethnicities in Singapore and revealed a Malay-related novel ancestry component. Furthermore, demographic inference suggested that Malays split from Chinese ∼24,800 years ago and experienced significant admixture with East Asians ∼1,700 years ago, coinciding with the Austronesian expansion. Additionally, we identified 20 candidate loci for natural selection, 14 of which harbored robust associations with complex traits and diseases. Finally, we show that our data can substantially improve genotype imputation in diverse Asian and Oceanian populations. These results highlight the value of our data as a resource to empower human genetics discovery across broad geographic regions. Agency for Science, Technology and Research (A*STAR) National Medical Research Council (NMRC) National Research Foundation (NRF) Accepted version We acknowledge H.M. Kang, S. Das, A. Tan, F. Zhang, J. Terhorst, P.-R. Loh, and G. Hellenthal for helpful discussions and support from all participants and clinical research coordinators of the contributing cohorts and studies: the TTSH Healthy Control Workgroup, the SEED cohort, the Asian Sudden Cardiac Death in Heart Failure Study, the Singapore Heart Failure Outcomes and Phenotypes (SHOP) cohort, the Asian neTwork for Translational Research and Cardiovascular Trials (ATTRaCT), the Parkinson’s Disease Study, the Peranakan Genome Study, the Platinum Asian Genomes Project, the Bariatric Surgery Study, the National Heart Centre Singapore Biobank and SingHEART cohorts, and the GUSTO and S-PRESTO study groups. This study was supported by Singapore’s A*STAR (core funding and IAF-PP H17/01/a0/007), BMRC (SPF2014/001, SPF2013/002, SPF2014/003, SPF2014/004, and SPF2014/005), NMRC (CIRG/1371/2013, CIRG/1417/2015, CIRG/1488/ 2018, CSA-SI/0012/2017, CG/017/2013, CG/M006/2017_NHCS, TCR/013- NNI/2014, STaR/0011/2012, STaR2013/001, STaR/014/2013, STaR/0026/ 2015, TCR/006-NUHS/2013, TCR/012-NUHS/2014, TCR/004-NUS/2008, TCR/012-NUHS/2014, and center grants 2010-13 and 2013-2017), NRF (NRFF2016-03), National University of Singapore, SingHealth and DukeNUS, and Alexandra Health small innovative grant SIGII/15203 and funding from Huazhong University of Science and Technology, the Tanoto Foundation, the Lee Foundation, the Boston Scientific Investigator Sponsored Research Program and Bayer, the NSF (DEB-1753489), and the Alfred P. Sloan Foundation. The computation was partially performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg).

Published
2019

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