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1. The NITRATE-OCT study-inorganic nitrate reduces in-stent restenosis in patients with stable coronary artery disease: a double-blind, randomised controlled trialResearch in context

Author

Krishnaraj S. Rathod, Anthony Mathur, Asad Shabbir, Rayomand S. Khambata, Clement Lau, Anne-Marie Beirne, Ismita Chhetri, Mutsumi Ono, Djouhar R. Belgaid, Gianmichele Massimo, Anantharaman Ramasamy, Vincenzo Tufaro, Ajay K. Jain, Neil Poulter, Emanuela Falaschetti, Daniel A. Jones, Hector M. Garcia-Garcia, Christos Bourantas, Anna Learoyd, Helen R. Warren, and Amrita Ahluwalia

Subjects
Coronary, Dietary, In-stent, Nitric oxide, PCI, Restenosis, Medicine (General), R5-920
Abstract

Summary: Background: Coronary angioplasty and stent insertion is a first line treatment for patients with coronary artery disease, however it is complicated in the long-term by in-stent restenosis (ISR) in a proportion of patients with an associated morbidity. Despite this, currently there are no effective treatments available for the prevention of ISR. Repeat percutaneous revascularisation carries increased risks of major adverse cardiovascular events and a higher incidence of stent failure. In this study we report the efficacy of dietary inorganic nitrate in the prevention of ISR in a prospective, double-blind, randomised controlled trial. Methods: NITRATE-OCT is a double-blind, randomised, single-centre, placebo-controlled phase II trial. 300 patients who were planned to undergo percutaneous coronary intervention (PCI) and drug eluting stent (DES) implantation for stable angina were randomised on a 1:1 basis to receive a daily dose of either dietary inorganic nitrate or placebo for 6 months. Block randomisation was used and patients stratified according to diabetes status. The patients then underwent quantitative coronary angiography (QCA) at baseline and at 6 months and optical coherence tomography at 6 months to quantify ISR. The primary endpoint was the QCA quantified decrease of in-stent/in-segment diameter from the baseline measure at 6 months i.e., in-stent and in-segment late-lumen loss (LLL). The study is registered with ClinicalTrials.gov, number NCT02529189. Findings: From November 1st 2015 and March 31st 2020, NITRATE-OCT enrolled 300 patients with angina, with 150 each randomised to receive 70 mL of nitrate-containing beetroot juice or placebo (nitrate-deplete) juice for 6 months. Procedural characteristics were similar between the groups. The primary endpoint was available in 208 patients: 107 and 101 in the nitrate and placebo groups, respectively. There was a statistically significant effect of inorganic nitrate on both primary endpoints: in-stent LLL decreased by 0.16 mm (95% CI:0.06–0.25; P = 0.001) with mean = 0.09 ± 0.38 mm in the inorganic nitrate group versus 0.24 ± 0.33 mm in the placebo group; (P = 0.0052); and in-segment LLL decreased by 0.24 mm (95% CI:0.12–0.36; P

Published
2024
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2. Treatment optimisation for blood pressure with single-pill combinations in India (TOPSPIN) – Protocol design and baseline characteristics

Author

Gaia Kiru, Ambuj Roy, Dimple Kondal, Ambalam M. Chandrasekaran, Somnath Mukherjee, Bishav Mohan, Kavita Singh, Hyndavi Salwa, Edmin Christa, Ameeka Shereen Lobo, Gayatri Mahajan, Aman Khanna, Amit Malviya, Satish G. Patil, Vinod K. Abichandani, Bhupinder Singh, Bal Kishan Gupta, Balsubramaiam Yellapantula, Dandge Shailendra, Shantanu Sengupta, Sunil Kumar, Neil Bardoloi, Mallika Khanna, Animesh Mishra, Kiran Aithal, Vipul Chavda, Victoria R. Cornelius, Dorairaj Prabhakaran, and Neil Poulter

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: The burden of over 300 million individuals living with hypertension in India is increasing steadily. Most current guidelines recommend initial combination therapy for effective blood pressure (BP) control. However, there is no randomised evidence to inform which combinations to use in the South Asian population, who account for over one-quarter of the world's population. Methods: This multi-centre, single-blind, randomised, three-arm trial recruited men and women aged 30–79 years with hypertension. The trial compares the efficacy of commonly recommended single pill combinations (SPCs) of three drug classes – calcium channel blocker (amlodipine), ACE inhibitor (perindopril), and a thiazide-like diuretic (indapamide). The primary objective is to determine the most effective two-drug combination, initially at starting doses with forced up-titration at 2 months, in reducing 24-h ambulatory systolic blood pressure (ASBP) at 6 months. The trial has 85 % power to detect a difference of 3 mmHg in 24-h ASBP amongst the groups.Participant recruitment took place from August 2022 to February 2024. Baseline results: The 1981 participants (42.0 % women) enrolled had a mean age of 52.1 (SD 11.3) years and a mean body mass index of 26.5 (SD 4.2) kg/m2. 58.1 % of participants had a previous diagnosis of hypertension and 18.6 % of participants were known to diabetes. The mean ASBP was 135.6 (SD 17.0) mmHg, and the mean ambulatory diastolic BP was 84.5 (SD 10.9) mmHg. Conclusion: The TOPSPIN trial is the first randomised evaluation of commonly used BP-lowering combination therapies in a South Asian population. The results have potentially significant implications for choosing first-line antihypertensive agents among Indians and the South Asian diaspora.

Published
2024
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3. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author

Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, and Gina M. Peloso

Subjects
Cholesterol, Lipids, Genetics, Genome-wide association study, GWAS, Biology (General), QH301-705.5, QH426-470
Abstract

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Published
2022
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4. Rationale for a New Low-Dose Triple Single Pill Combination for the Treatment of Hypertension

Author

Anthony Rodgers, Abdul Salam, William Cushman, Asita de Silva, Gian Luca Di Tanna, Sonali R. Gnanenthiran, Diederick Grobbee, Krzysztof Narkiewicz, Dike Ojji, Suzanne Oparil, Neil Poulter, Markus P. Schlaich, Aletta E. Schutte, Wilko Spiering, Bryan Williams, Jackson T. Wright, and Paul Whelton

Subjects
hypertension, polypill, blood pressure, single pill combination, fixed dose, Diseases of the circulatory (Cardiovascular) system, RC666-701, Public aspects of medicine, RA1-1270
Abstract

Two recent large trials showed the potential of single pill combinations (SPCs) with ≥3 low-dose components among people with hypertension who were untreated or receiving monotherapy. In both trials, these ‘hypertension polypills’ were superior to usual care, achieving >80% BP control without increasing withdrawal due to side effects. However, there are no such products available for prescribers. To address this unmet need, George Medicines developed GMRx2 with telmisartan/amlodipine/indapamide in three strengths (mg): 10/1.25/0.625, 20/2.5/1.25; 40/5/2.5. Two pivotal trials are ongoing to support FDA submission for the treatment of hypertension, including initial treatment. These assess efficacy and safety of GMRx2 compared to: placebo, and each of the three possible dual combinations. Regulatory submissions are planned for 2024, with the aim of providing access to GMRx2 in developed and developing regions. Wider implementation of GMRx2-based treatment strategies will be guided by further research to inform access and appropriate scale up.

Published
2024
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5. Variation in hypertension clinical practice guidelines: a global comparison

Author

Richu Philip, Thomas Beaney, Nick Appelbaum, Carmen Rodriguez Gonzalvez, Charlotte Koldeweij, Amelia Kataria Golestaneh, Neil Poulter, and Jonathan M. Clarke

Subjects
Medicine
Abstract

Abstract Background Hypertension is the largest single contributor to the global burden of disease, affecting an estimated 1.39 billion people worldwide. Clinical practice guidelines (CPGs) can aid in the effective management of this common condition, however, inconsistencies exist between CPGs, and the extent of this is unknown. Understanding the differences in CPG recommendations across income settings may provide an important means of understanding some of the global variations in clinical outcomes related to hypertension. Aims This study aims to analyse the variation between hypertension CPGs globally. It aims to assess the variation in three areas: diagnostic threshold and staging, treatment and target blood pressure (BP) recommendations in hypertension. Methods A search was conducted on the MEDLINE repository to identify national and international hypertension CPGs from 2010 to May 2020. An additional country-specific grey-literature search was conducted for all countries and territories of the world as identified by the World Bank. Data describing the diagnosis, staging, treatment and target blood pressure were extracted from CPGs, and variations between CPGs for these domains were analysed. Results Forty-eight CPGs from across all World Bank income settings were selected for analysis. Ninety-six per cent of guidelines defined hypertension as a clinic-based BP of ≥140/90 mmHg, and 87% of guidelines recommended a target BP of

Published
2021
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6. High prevalence of non-dipping patterns among Black Africans with uncontrolled hypertension: a secondary analysis of the CREOLE trial

Author

Prossie Merab Ingabire, Dike B. Ojji, Brian Rayner, Elijah Ogola, Albertino Damasceno, Erika Jones, Anastase Dzudie, Okechukwu S. Ogah, Neil Poulter, Mahmoud U. Sani, Felix Ayub Barasa, Grace Shedul, John Mukisa, David Mukunya, Bonnie Wandera, Charles Batte, James Kayima, Shahiemah Pandie, Charles Kiiza Mondo, and CREOLE Study Investigators

Subjects
Non-dipping pattern, Dipping pattern, Uncontrolled hypertension, Black African, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Background Dipping of blood pressure (BP) at night is a normal physiological phenomenon. However, a non-dipping pattern is associated with hypertension mediated organ damage, secondary forms of hypertension and poorer long-term outcome. Identifying a non-dipping pattern may be useful in assessing risk, aiding the decision to investigate for secondary causes, initiating treatment, assisting decisions on choice and timing of antihypertensive therapy, and intensifying salt restriction. Objectives To estimate the prevalence and factors associated with non-dipping pattern and determine the effect of 6 months of three antihypertensive regimens on the dipping pattern among Black African hypertensive patients. Methods This was a secondary analysis of the CREOLE Study which was a randomized, single blind, three-group trial conducted in 10 sites in 6 Sub-Saharan African countries. The participants were 721 Black African patients, aged between 30 and 79 years, with uncontrolled hypertension and a baseline 24-h ambulatory blood pressure monitoring (ABPM). Dipping was calculated from the average day and average night systolic blood pressure measures. Results The prevalence of non-dipping pattern was 78% (564 of 721). Factors that were independently associated with non-dipping were: serum sodium > 140 mmol/l (OR = 1.72, 95% CI 1.17–2.51, p-value 0.005), a higher office systolic BP (OR = 1.03, 95% CI 1.01–1.05, p-value 0.003) and a lower office diastolic BP (OR = 0.97, 95% CI 0.95–0.99, p-value 0.03). Treatment allocation did not change dipping status at 6 months (McNemar’s Chi2 0.71, p-value 0.40). Conclusion There was a high prevalence of non-dipping among Black Africans with uncontrolled hypertension. ABPM should be considered more routinely in Black Africans with uncontrolled hypertension, if resources permit, to help personalise therapy. Further research is needed to understand the mechanisms and causes of non-dipping pattern and if targeting night-time BP improves clinical outcomes. Trial registration ClinicalTrials.gov (NCT02742467).

Published
2021
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7. Comparison of Circulating Biomarkers in Predicting Diabetic Kidney Disease Progression With Autoantibodies to Erythropoietin Receptor

Author

Megumi Oshima, Akinori Hara, Tadashi Toyama, Min Jun, Carol Pollock, Meg Jardine, Stephen Harrap, Neil Poulter, Mark E. Cooper, Mark Woodward, John Chalmers, Vlado Perkovic, Muh Geot Wong, and Takashi Wada

Subjects
biomarker, end-stage kidney disease, type 2 diabetes, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Introduction: Several circulating markers, including autoantibodies to erythropoietin receptor (anti-EPOR antibodies), have been identified as useful biomarkers in predicting diabetic kidney disease progression. However, a direct comparison of their utility is lacking. We aimed to validate and to compare the prognostic value of anti-EPOR antibodies with that of other known biomarkers, using the ADVANCE trial and its long-term follow-up, ADVANCE-ON, cohorts. Methods: In this nested case-control study from the ADVANCE trial cohort, we included 165 case participants who had the composite kidney outcome (renal replacement therapy, renal death, or doubling of serum creatinine to ≥200 μmol/l) and 330 matched controls. We compared the associations of baseline plasma levels of anti-EPOR antibodies, tumor necrosis factor receptor (TNFR)-1 and -2, and bone morphogenetic protein (BMP)-7 with kidney outcomes. Results: Cases had higher baseline plasma levels of anti-EPOR antibodies than controls (median 1.7 vs. 0.6 enzyme-linked immunosorbent assay unit, P < 0.001). Higher levels of anti-EPOR antibodies were associated with an increased risk of kidney outcome (odds ratio 2.16 [95% confidence interval 1.51, 3.08], per 1 SD of log-transformed levels) after adjusting for conventional markers. Elevated circulating TNFR1 and TNFR2 levels, and lower BMP-7 levels at baseline, were associated with poor kidney outcome (odds ratios 2.06 [1.29, 3.30], 1.66 [1.13, 2.43], and 0.45 [0.32, 0.65], respectively). The addition of anti-EPOR antibodies into the model improved the prediction of kidney outcome, regardless of other biomarkers. Conclusion: Anti-EPOR antibodies provide a promising biomarker, as with TNFR1, TNFR2, and BMP-7, in predicting kidney disease progression in people with type 2 diabetes mellitus.

Published
2021
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8. History of lower-limb complications and risk of cancer death in people with type 2 diabetes

Author

Kamel Mohammedi, Stephen Harrap, Giuseppe Mancia, Michel Marre, Neil Poulter, John Chalmers, and Mark Woodward

Subjects
Cancers, Cancer death, Lower-limb complication, Peripheral arterial disease, Peripheral neuropathy, Type 2 diabetes, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Background Individuals with diabetes and lower-limb complications are at high risk for cardiovascular and all-cause mortality, but uncertainties remain in terms of cancer-related death in this population. We investigated this relationship in a large cohort of people with type 2 diabetes. Methods We used data from the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) study. The primary outcome was adjudicated cancer death; secondary outcomes were overall and site-specific incident cancers, determined according to the International Classification of Diseases Code (ICD-10). We compared outcomes in individuals with (versus without) a baseline history of lower-limb complications (peripheral artery disease (PAD) or sensory peripheral neuropathy) using Cox regression models. Results Among 11,140 participants (women 42%, mean age 66 years), lower-limb complications were reported at baseline in 4293 (38%) individuals: 2439 (22%) with PAD and 2973 (27%) with peripheral neuropathy. Cancer death occurred in 316 (2.8%) participants during a median of 5.0 (25th–75th percentile, 4.7–5.1) years of follow-up corresponding to 53,550 person-years and an incidence rate of 5.9 (95% CI 5.3–6.6) per 1000 person-years. The risk of cancer death was higher in individuals with (versus without) lower-limb complication [hazard ratio 1.53 (95% CI, 1.21–1.94), p = 0.0004], PAD [1.32 (1.02–1.70), p = 0.03] or neuropathy (1.41 (1.11–1.79), p = 0.004], adjusting for potential confounders and study allocations. PAD, but not neuropathy, was associated with excess risk of incident cancers. Conclusions PAD and peripheral neuropathy were independently associated with increased 5-year risk of cancer death in individuals with type 2 diabetes. PAD was also associated with increased risk of incident cancers. Our findings provide new evidence on the non-cardiovascular prognostic burden of lower-limb complications in people with type 2 diabetes.

Published
2021
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9. Declaración de posición del Grupo de la Comisión Lancet de Hipertensión con respecto a la mejora mundial de las normas de exactitud para los dispositivos de medición de la presión arterial

Author

James E. Sharman, Eoin O’Brien, Bruce Alpert, Aletta E. Schutte, Christian Delles, Michael Hecht Olsen, Roland Asmar, Neil Atkins, Eduardo Barbosa, David Calhoun, Norm R.C. Campbell, John Chalmers, Ivor Benjamin, Garry Jennings, Stéphane Laurent, Pierre Boutouyrie, Patricio Lopez-Jaramillo, Richard J. McManus, Anastasia S. Mihailidou, Pedro Ordunez, Raj Padwal, Paolo Palatini, Gianfranco Parati, Neil Poulter, Michael K. Rakotz, Clive Rosendorff, Francesca Saladini, Angelo Scuteri, Weimar Sebba Barroso, Myeong-Chan Cho, Ki-Chul Sung, Raymond R. Townsend, Ji-Guang Wang, Tine Willum Hansen, Gregory Wozniak, and George Stergiou

Subjects
salud internacional, tecnología biomédica, estándares de referencia, equipos diagnósticos, Medicine, Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract

La Comisión Lancet de Hipertensión determinó que una medida clave para responder a la carga mundial que representa la hipertensión arterial era mejorar la calidad de las mediciones de la presión arterial, mediante la utilización de dispositivos cuya exactitud haya sido validada. En la actualidad existen 3000 dispositivos comercializados, pero muchos no tienen datos publicados sobre pruebas de exactitud conformes a las normas científicas establecidas. La falta de regulación o su ineficiencia, que permiten la autorización de dispositivos para uso comercial sin una validación oficial, posibilitan este problema. Además, han surgido tecnologías nuevas de medición de la presión arterial (por ejemplo, los sensores sin brazalete) sobre las cuales no existe unanimidad en la comunidad científica con respecto a las normas de exactitud de la medición. En conjunto, estos aspectos contribuyen a la disponibilidad generalizada de tensiómetros de consultorio o domiciliarios que ofrecen una exactitud limitada o incierta, que llevan a diagnósticos, manejo y farmacoterapia inapropiados de la hipertensión a escala mundial. Los problemas más importantes relacionados con la exactitud de los dispositivos de medición de la presión arterial se pueden resolver mediante el requisito regulatorio de una validación independiente obligatoria de los dispositivos, en consonancia con la norma ISO universalmente aceptada. Esta es una recomendación básica y constituye una necesidad internacional acuciante. Otras recomendaciones clave son la elaboración de normas de validación específicas para las tecnologías nuevas de medición de la presión arterial y la publicación en línea de listas de los dispositivos nuevos exactos que están a la disposición de los usuarios y los profesionales de salud. Las recomendaciones están en consonancia con las políticas de la Organización Mundial de la Salud sobre los dispositivos médicos y la atención universal de la salud. El cumplimiento de las recomendaciones aumentará la disponibilidad mundial de dispositivos de medición de la presión arterial que sean exactos y tendrá como efecto un mejor diagnóstico y tratamiento, reduciendo así la carga mundial de la hipertensión.

Published
2020
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10. World Heart Federation Roadmap for Hypertension – A 2021 Update

Author

Panniyammakal Jeemon, Tania Séverin, Celso Amodeo, Dina Balabanova, Norm R. C. Campbell, Dan Gaita, Kazuomi Kario, Taskeen Khan, Rita Melifonwu, Andrew Moran, Elijah Ogola, Pedro Ordunez, Pablo Perel, Daniel Piñeiro, Fausto J. Pinto, Aletta E. Schutte, Fernando Stuardo Wyss, Lijing L. Yan, Neil Poulter, and Dorairaj Prabhakaran

Subjects
world heart federation, whf, hypertension, raised blood pressure, raised bp, policy background, Diseases of the circulatory (Cardiovascular) system, RC666-701, Public aspects of medicine, RA1-1270
Abstract

The World Heart Federation (WHF) Roadmap series covers a large range of cardiovascular conditions. These Roadmaps identify potential roadblocks and their solutions to improve the prevention, detection and management of cardiovascular diseases and provide a generic global framework available for local adaptation. A first Roadmap on raised blood pressure was published in 2015. Since then, advances in hypertension have included the publication of new clinical guidelines (AHA/ACC; ESC; ESH/ISH); the launch of the WHO Global HEARTS Initiative in 2016 and the associated Resolve to Save Lives (RTSL) initiative in 2017; the inclusion of single-pill combinations on the WHO Essential Medicines’ list as well as various advances in technology, in particular telemedicine and mobile health. Given the substantial benefit accrued from effective interventions in the management of hypertension and their potential for scalability in low and middle-income countries (LMICs), the WHF has now revisited and updated the ‘Roadmap for raised BP’ as ‘Roadmap for hypertension’ by incorporating new developments in science and policy. Even though cost-effective lifestyle and medical interventions to prevent and manage hypertension exist, uptake is still low, particularly in resource-poor areas. This Roadmap examined the roadblocks pertaining to both the demand side (demographic and socio-economic factors, knowledge and beliefs, social relations, norms, and traditions) and the supply side (health systems resources and processes) along the patient pathway to propose a range of possible solutions to overcoming them. Those include the development of population-wide prevention and control programmes; the implementation of opportunistic screening and of out-of-office blood pressure measurements; the strengthening of primary care and a greater focus on task sharing and team-based care; the delivery of people-centred care and stronger patient and carer education; and the facilitation of adherence to treatment. All of the above are dependent upon the availability and effective distribution of good quality, evidencebased, inexpensive BP-lowering agents.

Published
2021
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11. Associations of autozygosity with a broad range of human phenotypes

Author

David W Clark, Yukinori Okada, Kristjan H S Moore, Dan Mason, Nicola Pirastu, Ilaria Gandin, Hannele Mattsson, Catriona L K Barnes, Kuang Lin, Jing Hua Zhao, Patrick Deelen, Rebecca Rohde, Claudia Schurmann, Xiuqing Guo, Franco Giulianini, Weihua Zhang, Carolina Medina-Gomez, Robert Karlsson, Yanchun Bao, Traci M Bartz, Clemens Baumbach, Ginevra Biino, Matthew J Bixley, Marco Brumat, Jin-Fang Chai, Tanguy Corre, Diana L Cousminer, Annelot M Dekker, David A Eccles, Kristel R van Eijk, Christian Fuchsberger, He Gao, Marine Germain, Scott D Gordon, Hugoline G de Haan, Sarah E Harris, Edith Hofer, Alicia Huerta-Chagoya, Catherine Igartua, Iris E Jansen, Yucheng Jia, Tim Kacprowski, Torgny Karlsson, Marcus E Kleber, Shengchao Alfred Li, Ruifang Li-Gao, Anubha Mahajan, Koichi Matsuda, Karina Meidtner, Weihua Meng, May E Montasser, Peter J van der Most, Matthias Munz, Teresa Nutile, Teemu Palviainen, Gauri Prasad, Rashmi B Prasad, Tallapragada Divya Sri Priyanka, Federica Rizzi, Erika Salvi, Bishwa R Sapkota, Daniel Shriner, Line Skotte, Melissa C Smart, Albert Vernon Smith, Ashley van der Spek, Cassandra N Spracklen, Rona J Strawbridge, Salman M Tajuddin, Stella Trompet, Constance Turman, Niek Verweij, Clara Viberti, Lihua Wang, Helen R Warren, Robyn E Wootton, Lisa R Yanek, Jie Yao, Noha A Yousri, Wei Zhao, Adebowale A Adeyemo, Saima Afaq, Carlos Alberto Aguilar-Salinas, Masato Akiyama, Matthew L Albert, Matthew A Allison, Maris Alver, Tin Aung, Fereidoun Azizi, Amy R Bentley, Heiner Boeing, Eric Boerwinkle, Judith B Borja, Gert J de Borst, Erwin P Bottinger, Linda Broer, Harry Campbell, Stephen Chanock, Miao-Li Chee, Guanjie Chen, Yii-Der I Chen, Zhengming Chen, Yen-Feng Chiu, Massimiliano Cocca, Francis S Collins, Maria Pina Concas, Janie Corley, Giovanni Cugliari, Rob M van Dam, Anna Damulina, Maryam S Daneshpour, Felix R Day, Graciela E Delgado, Klodian Dhana, Alexander S F Doney, Marcus Dörr, Ayo P Doumatey, Nduna Dzimiri, S Sunna Ebenesersdóttir, Joshua Elliott, Paul Elliott, Ralf Ewert, Janine F Felix, Krista Fischer, Barry I Freedman, Giorgia Girotto, Anuj Goel, Martin Gögele, Mark O Goodarzi, Mariaelisa Graff, Einat Granot-Hershkovitz, Francine Grodstein, Simonetta Guarrera, Daniel F Gudbjartsson, Kamran Guity, Bjarni Gunnarsson, Yu Guo, Saskia P Hagenaars, Christopher A Haiman, Avner Halevy, Tamara B Harris, Mehdi Hedayati, David A van Heel, Makoto Hirata, Imo Höfer, Chao Agnes Hsiung, Jinyan Huang, Yi-Jen Hung, M Arfan Ikram, Anuradha Jagadeesan, Pekka Jousilahti, Yoichiro Kamatani, Masahiro Kanai, Nicola D Kerrison, Thorsten Kessler, Kay-Tee Khaw, Chiea Chuen Khor, Dominique P V de Kleijn, Woon-Puay Koh, Ivana Kolcic, Peter Kraft, Bernhard K Krämer, Zoltán Kutalik, Johanna Kuusisto, Claudia Langenberg, Lenore J Launer, Deborah A Lawlor, I-Te Lee, Wen-Jane Lee, Markus M Lerch, Liming Li, Jianjun Liu, Marie Loh, Stephanie J London, Stephanie Loomis, Yingchang Lu, Jian’an Luan, Reedik Mägi, Ani W Manichaikul, Paolo Manunta, Gísli Másson, Nana Matoba, Xue W Mei, Christa Meisinger, Thomas Meitinger, Massimo Mezzavilla, Lili Milani, Iona Y Millwood, Yukihide Momozawa, Amy Moore, Pierre-Emmanuel Morange, Hortensia Moreno-Macías, Trevor A Mori, Alanna C Morrison, Taulant Muka, Yoshinori Murakami, Alison D Murray, Renée de Mutsert, Josyf C Mychaleckyj, Mike A Nalls, Matthias Nauck, Matt J Neville, Ilja M Nolte, Ken K Ong, Lorena Orozco, Sandosh Padmanabhan, Gunnar Pálsson, James S Pankow, Cristian Pattaro, Alison Pattie, Ozren Polasek, Neil Poulter, Peter P Pramstaller, Lluis Quintana-Murci, Katri Räikkönen, Sarju Ralhan, Dabeeru C Rao, Wouter van Rheenen, Stephen S Rich, Paul M Ridker, Cornelius A Rietveld, Antonietta Robino, Frank J A van Rooij, Daniela Ruggiero, Yasaman Saba, Charumathi Sabanayagam, Maria Sabater-Lleal, Cinzia Felicita Sala, Veikko Salomaa, Kevin Sandow, Helena Schmidt, Laura J Scott, William R Scott, Bahareh Sedaghati-Khayat, Bengt Sennblad, Jessica van Setten, Peter J Sever, Wayne H-H Sheu, Yuan Shi, Smeeta Shrestha, Sharvari Rahul Shukla, Jon K Sigurdsson, Timo Tonis Sikka, Jai Rup Singh, Blair H Smith, Alena Stančáková, Alice Stanton, John M Starr, Lilja Stefansdottir, Leon Straker, Patrick Sulem, Gardar Sveinbjornsson, Morris A Swertz, Adele M Taylor, Kent D Taylor, Natalie Terzikhan, Yih-Chung Tham, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Annika Tillander, Russell P Tracy, Teresa Tusié-Luna, Ioanna Tzoulaki, Simona Vaccargiu, Jagadish Vangipurapu, Jan H Veldink, Veronique Vitart, Uwe Völker, Eero Vuoksimaa, Salma M Wakil, Melanie Waldenberger, Gurpreet S Wander, Ya Xing Wang, Nicholas J Wareham, Sarah Wild, Chittaranjan S Yajnik, Jian-Min Yuan, Lingyao Zeng, Liang Zhang, Jie Zhou, Najaf Amin, Folkert W Asselbergs, Stephan J L Bakker, Diane M Becker, Benjamin Lehne, David A Bennett, Leonard H van den Berg, Sonja I Berndt, Dwaipayan Bharadwaj, Lawrence F Bielak, Murielle Bochud, Mike Boehnke, Claude Bouchard, Jonathan P Bradfield, Jennifer A Brody, Archie Campbell, Shai Carmi, Mark J Caulfield, David Cesarini, John C Chambers, Giriraj Ratan Chandak, Ching-Yu Cheng, Marina Ciullo, Marilyn Cornelis, Daniele Cusi, George Davey Smith, Ian J Deary, Rajkumar Dorajoo, Cornelia M van Duijn, David Ellinghaus, Jeanette Erdmann, Johan G Eriksson, Evangelos Evangelou, Michele K Evans, Jessica D Faul, Bjarke Feenstra, Mary Feitosa, Sylvain Foisy, Andre Franke, Yechiel Friedlander, Paolo Gasparini, Christian Gieger, Clicerio Gonzalez, Philippe Goyette, Struan F A Grant, Lyn R Griffiths, Leif Groop, Vilmundur Gudnason, Ulf Gyllensten, Hakon Hakonarson, Anders Hamsten, Pim van der Harst, Chew-Kiat Heng, Andrew A Hicks, Hagit Hochner, Heikki Huikuri, Steven C Hunt, Vincent W V Jaddoe, Philip L De Jager, Magnus Johannesson, Åsa Johansson, Jost B Jonas, J Wouter Jukema, Juhani Junttila, Jaakko Kaprio, Sharon L. R. Kardia, Fredrik Karpe, Meena Kumari, Markku Laakso, Sander W van der Laan, Jari Lahti, Matthias Laudes, Rodney A Lea, Wolfgang Lieb, Thomas Lumley, Nicholas G Martin, Winfried März, Giuseppe Matullo, Mark I McCarthy, Sarah E Medland, Tony R Merriman, Andres Metspalu, Brian F Meyer, Karen L Mohlke, Grant W Montgomery, Dennis Mook-Kanamori, Patricia B Munroe, Kari E North, Dale R Nyholt, Jeffery R O’connell, Carole Ober, Albertine J Oldehinkel, Walter Palmas, Colin Palmer, Gerard G Pasterkamp, Etienne Patin, Craig E Pennell, Louis Perusse, Patricia A Peyser, Mario Pirastu, Tinca J. C. Polderman, David J Porteous, Danielle Posthuma, Bruce M Psaty, John D Rioux, Fernando Rivadeneira, Charles Rotimi, Jerome I Rotter, Igor Rudan, Hester M Den Ruijter, Dharambir K Sanghera, Naveed Sattar, Reinhold Schmidt, Matthias B Schulze, Heribert Schunkert, Robert A Scott, Alan R Shuldiner, Xueling Sim, Neil Small, Jennifer A Smith, Nona Sotoodehnia, E-Shyong Tai, Alexander Teumer, Nicholas J Timpson, Daniela Toniolo, David-Alexandre Tregouet, Tiinamaija Tuomi, Peter Vollenweider, Carol A Wang, David R Weir, John B Whitfield, Cisca Wijmenga, Tien-Yin Wong, John Wright, Jingyun Yang, Lei Yu, Babette S Zemel, Alan B Zonderman, Markus Perola, Patrik K. E. Magnusson, André G Uitterlinden, Jaspal S Kooner, Daniel I Chasman, Ruth J. F. Loos, Nora Franceschini, Lude Franke, Chris S Haley, Caroline Hayward, Robin G Walters, John R. B. Perry, Tōnu Esko, Agnar Helgason, Kari Stefansson, Peter K Joshi, Michiaki Kubo, and James F Wilson

Subjects
Science
Abstract

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Published
2019
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12. Comparative effects of microvascular and macrovascular disease on the risk of major outcomes in patients with type 2 diabetes

Author

Kamel Mohammedi, Mark Woodward, Michel Marre, Stephen Colagiuri, Mark Cooper, Stephen Harrap, Giuseppe Mancia, Neil Poulter, Bryan Williams, Sophia Zoungas, and John Chalmers

Subjects
Type 2 diabetes, Microvascular disease, Macrovascular disease, Mortality, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Background Microvascular disease is associated with a high risk of macrovascular events in patients with type 2 diabetes, but the impact of macrovascular disease on the risk of microvascular events remains unknown. We sought to evaluate the respective effects of prior microvascular and macrovascular disease on the risk of major outcomes, including microvascular events, in these patients. Methods Participants in the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) trial (n = 11,140) and the ADVANCE-ON post-trial study (n = 8494) were categorized into 4 groups at baseline: dual absence of microvascular or macrovascular disease (n = 6789), presence of microvascular disease alone (n = 761), macrovascular disease alone (n = 3196), and both (n = 394). Outcomes were all-cause mortality, major macrovascular events (MACE), and major clinical microvascular events. Results All-cause mortality, MACE, and major clinical microvascular events occurred in 2265 (20%), 2166 (19%), and 807 (7%) participants respectively, during a median follow-up of 9.9 (inter-quartile interval 5.6–10.9) years. The adjusted hazard ratios [95% CI] of death, MACE, and major clinical microvascular events were each greater in patients with baseline microvascular disease (1.43 [1.20–1.71], 1.64 [1.37–1.97], and 4.74 [3.86–5.82], respectively), macrovascular disease (1.43 [1.30–1.57], 2.04 [1.86–2.25], and 1.26 [1.06–1.51]) or both (2.01 [1.65–2.45], 2.92 [2.40–3.55], and 6.30 [4.93–8.06]) compared with those without these conditions. No interaction was observed between baseline microvascular and macrovascular disease for these events. The addition of microvascular disease (change in c-statistic [95% CI] 0.005 [0.002–0.008], p = 0.02) or macrovascular disease (0.005 [0.002–0.007], p

Published
2017
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14. Relationship Between Plasma 8‐OH‐Deoxyguanosine and Cardiovascular Disease and Survival in Type 2 Diabetes Mellitus: Results From the ADVANCE Trial

Author

Merlin C. Thomas, Mark Woodward, Qiang Li, Raelene Pickering, Christos Tikellis, Neil Poulter, Mark E. Cooper, Michel Marre, Sophia Zoungas, and John Chalmers

Subjects
cardiovascular outcomes, mortality, oxidative stress, survival analysis, type 2 diabetes mellitus, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background 8‐Oxo‐2′‐deoxyguanosine (8‐oxo‐2′‐dG) is a biomarker of oxidative DNA damage that is associated with cardiovascular disease and premature mortality in the general population. Although oxidative stress has a proven role in cardiovascular complications in diabetes mellitus, evidence for a relationship between plasma 8‐oxo‐2′‐dG and major cardiovascular outcomes in diabetes mellitus is weak. Methods and Results A case‐cohort study was performed in 3766 participants with prevalent diabetes mellitus in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial (ClinicalTrials.gov number NCT00145925). The hazard ratios for mortality and major acute cardiovascular events were derived using Cox regression models. During a median of 5 years of follow‐up, 695 (18.4%) participants in this enriched cohort died (including 354 deaths from cardiovascular disease). Individuals with higher levels of 8‐oxo‐2′‐dG were more likely to die. After adjusting for cardiovascular disease risk factors, the hazard ratio for a 1‐SD increase in plasma 8‐oxo‐2′‐dG was 1.10 (95% confidence interval, 1.01–1.20; P=0.03). This was driven by an independent association between plasma 8‐oxo‐2′‐dG and cardiovascular death (hazard ratio, 1.23; 95% confidence interval, 1.10–1.37 [P

Published
2018
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15. Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.

Author

Mary F Feitosa, Aldi T Kraja, Daniel I Chasman, Yun J Sung, Thomas W Winkler, Ioanna Ntalla, Xiuqing Guo, Nora Franceschini, Ching-Yu Cheng, Xueling Sim, Dina Vojinovic, Jonathan Marten, Solomon K Musani, Changwei Li, Amy R Bentley, Michael R Brown, Karen Schwander, Melissa A Richard, Raymond Noordam, Hugues Aschard, Traci M Bartz, Lawrence F Bielak, Rajkumar Dorajoo, Virginia Fisher, Fernando P Hartwig, Andrea R V R Horimoto, Kurt K Lohman, Alisa K Manning, Tuomo Rankinen, Albert V Smith, Salman M Tajuddin, Mary K Wojczynski, Maris Alver, Mathilde Boissel, Qiuyin Cai, Archie Campbell, Jin Fang Chai, Xu Chen, Jasmin Divers, Chuan Gao, Anuj Goel, Yanick Hagemeijer, Sarah E Harris, Meian He, Fang-Chi Hsu, Anne U Jackson, Mika Kähönen, Anuradhani Kasturiratne, Pirjo Komulainen, Brigitte Kühnel, Federica Laguzzi, Jian'an Luan, Nana Matoba, Ilja M Nolte, Sandosh Padmanabhan, Muhammad Riaz, Rico Rueedi, Antonietta Robino, M Abdullah Said, Robert A Scott, Tamar Sofer, Alena Stančáková, Fumihiko Takeuchi, Bamidele O Tayo, Peter J van der Most, Tibor V Varga, Veronique Vitart, Yajuan Wang, Erin B Ware, Helen R Warren, Stefan Weiss, Wanqing Wen, Lisa R Yanek, Weihua Zhang, Jing Hua Zhao, Saima Afaq, Najaf Amin, Marzyeh Amini, Dan E Arking, Tin Aung, Eric Boerwinkle, Ingrid Borecki, Ulrich Broeckel, Morris Brown, Marco Brumat, Gregory L Burke, Mickaël Canouil, Aravinda Chakravarti, Sabanayagam Charumathi, Yii-Der Ida Chen, John M Connell, Adolfo Correa, Lisa de Las Fuentes, Renée de Mutsert, H Janaka de Silva, Xuan Deng, Jingzhong Ding, Qing Duan, Charles B Eaton, Georg Ehret, Ruben N Eppinga, Evangelos Evangelou, Jessica D Faul, Stephan B Felix, Nita G Forouhi, Terrence Forrester, Oscar H Franco, Yechiel Friedlander, Ilaria Gandin, He Gao, Mohsen Ghanbari, Bruna Gigante, C Charles Gu, Dongfeng Gu, Saskia P Hagenaars, Göran Hallmans, Tamara B Harris, Jiang He, Sami Heikkinen, Chew-Kiat Heng, Makoto Hirata, Barbara V Howard, M Arfan Ikram, InterAct Consortium, Ulrich John, Tomohiro Katsuya, Chiea Chuen Khor, Tuomas O Kilpeläinen, Woon-Puay Koh, José E Krieger, Stephen B Kritchevsky, Michiaki Kubo, Johanna Kuusisto, Timo A Lakka, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Benjamin Lehne, Cora E Lewis, Yize Li, Shiow Lin, Jianjun Liu, Jingmin Liu, Marie Loh, Tin Louie, Reedik Mägi, Colin A McKenzie, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Lili Milani, Karen L Mohlke, Yukihide Momozawa, Mike A Nalls, Christopher P Nelson, Nona Sotoodehnia, Jill M Norris, Jeff R O'Connell, Nicholette D Palmer, Thomas Perls, Nancy L Pedersen, Annette Peters, Patricia A Peyser, Neil Poulter, Leslie J Raffel, Olli T Raitakari, Kathryn Roll, Lynda M Rose, Frits R Rosendaal, Jerome I Rotter, Carsten O Schmidt, Pamela J Schreiner, Nicole Schupf, William R Scott, Peter S Sever, Yuan Shi, Stephen Sidney, Mario Sims, Colleen M Sitlani, Jennifer A Smith, Harold Snieder, John M Starr, Konstantin Strauch, Heather M Stringham, Nicholas Y Q Tan, Hua Tang, Kent D Taylor, Yik Ying Teo, Yih Chung Tham, Stephen T Turner, André G Uitterlinden, Peter Vollenweider, Melanie Waldenberger, Lihua Wang, Ya Xing Wang, Wen Bin Wei, Christine Williams, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Alan B Zonderman, Diane M Becker, Michael Boehnke, Donald W Bowden, John C Chambers, Ian J Deary, Tõnu Esko, Martin Farrall, Paul W Franks, Barry I Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Jost Bruno Jonas, Yoichiro Kamatani, Norihiro Kato, Jaspal S Kooner, Zoltán Kutalik, Markku Laakso, Cathy C Laurie, Karin Leander, Terho Lehtimäki, Lifelines Cohort Study, Patrik K E Magnusson, Albertine J Oldehinkel, Brenda W J H Penninx, Ozren Polasek, David J Porteous, Rainer Rauramaa, Nilesh J Samani, James Scott, Xiao-Ou Shu, Pim van der Harst, Lynne E Wagenknecht, Nicholas J Wareham, Hugh Watkins, David R Weir, Ananda R Wickremasinghe, Tangchun Wu, Wei Zheng, Claude Bouchard, Kaare Christensen, Michele K Evans, Vilmundur Gudnason, Bernardo L Horta, Sharon L R Kardia, Yongmei Liu, Alexandre C Pereira, Bruce M Psaty, Paul M Ridker, Rob M van Dam, W James Gauderman, Xiaofeng Zhu, Dennis O Mook-Kanamori, Myriam Fornage, Charles N Rotimi, L Adrienne Cupples, Tanika N Kelly, Ervin R Fox, Caroline Hayward, Cornelia M van Duijn, E Shyong Tai, Tien Yin Wong, Charles Kooperberg, Walter Palmas, Kenneth Rice, Alanna C Morrison, Paul Elliott, Mark J Caulfield, Patricia B Munroe, Dabeeru C Rao, Michael A Province, and Daniel Levy

Subjects
Medicine, Science
Abstract

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

Published
2018
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16. Prognostic Impact of In‐Hospital and Postdischarge Heart Failure in Patients With Acute Myocardial Infarction: A Nationwide Analysis Using Data From the Cardiovascular Disease in Norway (CVDNOR) Project

Author

Gerhard Sulo, Jannicke Igland, Ottar Nygård, Stein Emil Vollset, Marta Ebbing, Neil Poulter, Grace M. Egeland, Charlotte Cerqueira, Torben Jørgensen, and Grethe S. Tell

Subjects
acute myocardial infarction, CVDNOR, heart failure, mortality, Norway, trends, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background Heart failure (HF) is a serious complication of acute myocardial infarction (AMI). We explored the excess mortality associated with HF as an early or late complication of AMI and describe changes over time in such excess mortality. Methods and Results All patients hospitalized with an incident AMI and without history of prior HF hospitalization were followed up to 1 year after AMI discharge for episodes of HF. New HF episodes were classified as in‐hospital HF if diagnosed during the AMI hospitalization or postdischarge HF if diagnosed within 1 year after discharge from the incident AMI. Logistic and Cox regression models were used to explore the excess mortality associated with HF categories. Changes over time in the excess mortality were assessed by testing the interaction between HF status and study year. In‐hospital HF increased in‐hospital mortality 1.79 times (odds ratio [OR], 1.79; 95% CI: 1.68–1.91). The excess mortality associated with HF increased by 4.3 times from 2001 to 2009 (P interaction

Published
2017
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17. An evaluation of the effect of an angiotensin-converting enzyme inhibitor on the growth rate of small abdominal aortic aneurysms: a randomised placebo-controlled trial (AARDVARK)

Author

Gaia Kiru, Colin Bicknell, Emanuela Falaschetti, Janet Powell, Neil Poulter, and on behalf of the AARDVARK collaborators

Subjects
abdominal aortic aneurysm, angiotensin-converting enzyme inhibition, perindopril, growth, blood pressure lowering, calcium channel blocker, randomised controlled trial, Medical technology, R855-855.5
Abstract

Background: Although data are inconsistent, angiotensin-converting enzyme inhibitors (ACE-Is) have been associated with a reduced incidence of abdominal aortic aneurysm (AAA) rupture in analysis of administrative databases. Objectives: (1) To investigate whether or not the ACE-I perindopril (Coversyl arginine, Servier) reduces small AAA growth rate and (2) to evaluate blood pressure (BP)-independent effects of perindopril on small AAA growth and to compare the repeatability of measurement of internal and external aneurysm diameters. Design: A three-arm, multicentre, single-blind, randomised placebo-controlled trial. Setting: Fourteen hospitals in England. Participants: Men or women aged ≥ 55 years with an AAA of 3.0–5.4 cm in diameter by internal or external measurement according to ultrasonography and who met the trial eligibility criteria. Interventions: Patients were randomised to receive 10 mg of perindopril arginine daily, 5 mg of the calcium channel blocker amlodipine daily or placebo daily. Main outcome measures: The primary outcome was AAA diameter growth using external measurements in the longitudinal plane, which in-trial studies suggested was the preferred measure. Secondary outcome measures included AAA rupture, AAA repair, modelling of the time taken for the AAA to reach the threshold for intervention (5.5 cm) or referral for surgery, tolerance of study medication (measured by compliance, adverse events and quality of life) and a comparison of the repeatability of measures of internal and external AAA diameter. Patients were followed up every 3–6 months over 2 years. Results: In total, 227 patients were recruited and randomised into the three groups, which were generally well matched at baseline. Multilevel modelling was used to determine the maximum likelihood estimates for AAA diameter growth. No significant differences in the estimates of annual growth were apparent [1.68 (standard error 0.02) mm, 1.77 (0.02) mm and 1.81 (0.02) mm in the placebo, perindopril and amlodipine groups, respectively]. Similarly, no significant differences in the slopes of modelled growth over time were apparent between perindopril and placebo (p = 0.78) or between perindopril and amlodipine (p = 0.89). The results were essentially unaffected by adjustment for potential confounders. Compliance, measured by pill counts, was good throughout (> 80% at all visit time points). There were no significant in-trial safety concerns. Six patients withdrew because of adverse events attributed to the study medications (n = 2 perindopril, n = 4 amlodipine). No patients ruptured their AAA and 27 underwent elective surgery during the trial (n = 9 placebo, n = 10 perindopril, n = 8 amlodipine). Conclusions: We were unable to demonstrate a significant impact of perindopril compared with placebo or amlodipine on small AAA growth over a 2-year period. Furthermore, there were no differences in the times to reach a diameter of 5.5 cm or undergo surgery among the three groups. Perindopril and amlodipine were well tolerated by this population. External AAA measurements were found to be more repeatable than internal measurements. The observed AAA growth measurement variability was greater than that expected pre trial. This, combined with slower than expected mean growth rates, resulted in our having limited power to detect small differences between growth rates and hence this adds uncertainty to the interpretation of the results. Several further analyses are planned including a multivariate analysis of determinants of AAA growth, an evaluation of the possible differential effect of perindopril on fast AAA growth and an investigation into the roles of central BP and BP variability on AAA growth. Trial registration: Current Controlled Trials ISRCTN51383267. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 59. See the NIHR Journals Library website for further project information. The NIHR Biomedical Research Centre based at Imperial College NHS Trust supported the trial. Servier provided perindopril at no charge.

Published
2016
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18. Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a)

Author

Harshal A. Deshmukh, Helen M. Colhoun, Toby Johnson, Paul M. McKeigue, D. John Betteridge, Paul N. Durrington, John H. Fuller, Shona Livingstone, Valentine Charlton-Menys, Andrew Neil, Neil Poulter, Peter Sever, Denis C. Shields, Alice V. Stanton, Aurobindo Chatterjee, Craig Hyde, Roberto A. Calle, David A. DeMicco, Stella Trompet, Iris Postmus, Ian Ford, J. Wouter Jukema, Mark Caulfield, and Graham A. Hitman

Subjects
genetics, low density lipoprotein, LDL/metabolism, lipoprotein(a), statins, Biochemistry, QD415-436
Abstract

We carried out a genome-wide association study (GWAS) of LDL-c response to statin using data from participants in the Collaborative Atorvastatin Diabetes Study (CARDS; n = 1,156), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT; n = 895), and the observational phase of ASCOT (n = 651), all of whom were prescribed atorvastatin 10 mg. Following genome-wide imputation, we combined data from the three studies in a meta-analysis. We found associations of LDL-c response to atorvastatin that reached genome-wide significance at rs10455872 (P= 6.13 × 10−9) within the LPA gene and at two single nucleotide polymorphisms (SNP) within the APOE region (rs445925; P= 2.22 × 10−16 and rs4420638; P= 1.01 × 10−11) that are proxies for the ∊2 and ∊4 variants, respectively, in APOE. The novel association with the LPA SNP was replicated in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial (P= 0.009). Using CARDS data, we further showed that atorvastatin therapy did not alter lipoprotein(a) [Lp(a)] and that Lp(a) levels accounted for all of the associations of SNPs in the LPA gene and the apparent LDL-c response levels. However, statin therapy had a similar effect in reducing cardiovascular disease (CVD) in patients in the top quartile for serum Lp(a) levels (HR = 0.60) compared with those in the lower three quartiles (HR = 0.66; P= 0.8 for interaction). The data emphasize that high Lp(a) levels affect the measurement of LDL-c and the clinical estimation of LDL-c response. Therefore, an apparently lower LDL-c response to statin therapy may indicate a need for measurement of Lp(a). However, statin therapy seems beneficial even in those with high Lp(a).

Published
2012
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19. Control of Blood Pressure and Risk Attenuation: Post Trial Follow-Up of Randomized Groups.

Author

Tazeen H Jafar, Imtiaz Jehan, Feng Liang, Sylvaine Barbier, Muhammad Islam, Rasool Bux, Aamir Hameed Khan, Nivedita Nadkarni, Neil Poulter, Nish Chaturvedi, and Shah Ebrahim

Subjects
Medicine, Science
Abstract

Evidence on long term effectiveness of public health strategies for lowering blood pressure (BP) is scarce. In the Control of Blood Pressure and Risk Attenuation (COBRA) Trial, a 2 x 2 factorial, cluster randomized controlled trial, the combined home health education (HHE) and trained general practitioner (GP) intervention delivered over 2 years was more effective than no intervention (usual care) in lowering systolic BP among adults with hypertension in urban Pakistan. However, it was not clear whether the effect would be sustained after the cessation of intervention. We conducted 7 years follow-up inclusive of 5 years of post intervention period of COBRA trial participants to assess the effectiveness of the interventions on BP during extended follow-up.A total of 1341 individuals 40 years or older with hypertension (systolic BP 140 mm Hg or greater, diastolic BP 90 mm Hg or greater, or already receiving treatment) were followed by trained research staff masked to randomization status. BP was measured thrice with a calibrated automated device (Omron HEM-737 IntelliSense) in the sitting position after 5 minutes of rest. BP measurements were repeated after two weeks. Generalized estimating equations (GEE) were used to analyze the primary outcome of change in systolic BP from baseline to 7- year follow-up. The multivariable model was adjusted for clustering, age at baseline, sex, baseline systolic and diastolic BP, and presence of diabetes.After 7 years of follow-up, systolic BP levels among those randomised to combined HHE plus trained GP intervention were significantly lower (2.1 [4.1-0.1] mm Hg) compared to those randomised to usual care, (P = 0.04). Participants receiving the combined intervention compared to usual care had a greater reduction in LDL-cholesterol (2.7 [4.8 to 0.6] mg/dl.The benefit in systolic BP reduction observed in the original cohort assigned to the combined intervention was attenuated but still evident at 7- year follow-up. These findings highlight the potential for scaling-up simple strategies for cardiovascular risk reduction in low- and middle- income countries.ClinicalTrials.gov NCT00327574.

Published
2015
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20. Effects of the endpoint adjudication process on the results of a randomised controlled trial: the ADVANCE trial.

Author

Jun Hata, Hisatomi Arima, Sophia Zoungas, Greg Fulcher, Carol Pollock, Mark Adams, John Watson, Rohina Joshi, Andre Pascal Kengne, Toshiharu Ninomiya, Craig Anderson, Mark Woodward, Anushka Patel, Giuseppe Mancia, Neil Poulter, Stephen MacMahon, John Chalmers, Bruce Neal, and ADVANCE Collaborative Group

Subjects
Medicine, Science
Abstract

Endpoint adjudication committees (EPAC) are widely used in clinical trials. The aim of the present analysis is to assess the effects of the endpoint adjudication process on the main findings of the ADVANCE trial (Trial registration: ClinicalTrials.gov NCT00145925).The ADVANCE trial was a multicentre, 2 × 2 factorial randomised controlled trial of blood pressure lowering and intensive blood glucose control in 11140 patients with type 2 diabetes. Primary outcomes were major macrovascular (nonfatal myocardial infarction, nonfatal stroke and cardiovascular death) and microvascular (new or worsening nephropathy and retinopathy) events. Suspected primary outcomes were initially reported by the investigators at the 215 sites with subsequent adjudication by the EPAC. The EPAC also adjudicated upon potential events identified directly by ongoing screening of all reported events. Over a median follow-up of 5 years, the site investigators reported one or more primary outcomes among 2443 participants. After adjudication these events were confirmed for 2077 (85%) with 48 further events added through the EPAC-led database screening process. The estimated relative risk reductions (95% confidence intervals) in the primary outcome for the blood pressure lowering comparison were 8% (-1 to 15%) based on the investigator-reported events and 9% (0 to 17%) based on the EPAC-based events (P for homogeneity = 0.70). The corresponding findings for the glucose comparison were 8% (1 to 15%) and 10% (2% to 18%) (P for homogeneity = 0.60). The effect estimates were also highly comparable when studied separately for macrovascular events and microvascular events for both comparisons (all P for homogeneity>0.6).The endpoint adjudication process had no discernible impact on the main findings in ADVANCE. These data highlight the need for careful consideration of the likely impact of an EPAC on the findings and conclusions of clinical trials prior to their establishment.

Published
2013
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21. An international randomised placebo-controlled trial of a four-component combination pill ('polypill') in people with raised cardiovascular risk.

Author

PILL Collaborative Group, Anthony Rodgers, Anushka Patel, Otavio Berwanger, Michiel Bots, Richard Grimm, Diederick E Grobbee, Rod Jackson, Bruce Neal, Jim Neaton, Neil Poulter, Natasha Rafter, P Krishnam Raju, Srinath Reddy, Simon Thom, Stephen Vander Hoorn, and Ruth Webster

Subjects
Medicine, Science
Abstract

BackgroundThere has been widespread interest in the potential of combination cardiovascular medications containing aspirin and agents to lower blood pressure and cholesterol ('polypills') to reduce cardiovascular disease. However, no reliable placebo-controlled data are available on both efficacy and tolerability.MethodsWe conducted a randomised, double-blind placebo-controlled trial of a polypill (containing aspirin 75 mg, lisinopril 10 mg, hydrochlorothiazide 12.5 mg and simvastatin 20 mg) in 378 individuals without an indication for any component of the polypill, but who had an estimated 5-year cardiovascular disease risk over 7.5%. The primary outcomes were systolic blood pressure (SBP), LDL-cholesterol and tolerability (proportion discontinued randomised therapy) at 12 weeks follow-up.FindingsAt baseline, mean BP was 134/81 mmHg and mean LDL-cholesterol was 3.7 mmol/L. Over 12 weeks, polypill treatment reduced SBP by 9.9 (95% CI: 7.7 to 12.1) mmHg and LDL-cholesterol by 0.8 (95% CI 0.6 to 0.9) mmol/L. The discontinuation rates in the polypill group compared to placebo were 23% vs 18% (RR 1.33, 95% CI 0.89 to 2.00, p = 0.2). There was an excess of side effects known to the component medicines (58% vs 42%, p = 0.001), which was mostly apparent within a few weeks, and usually did not warrant cessation of trial treatment.ConclusionsThis polypill achieved sizeable reductions in SBP and LDL-cholesterol but caused side effects in about 1 in 6 people. The halving in predicted cardiovascular risk is moderately lower than previous estimates and the side effect rate is moderately higher. Nonetheless, substantial net benefits would be expected among patients at high risk.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12607000099426.

Published
2011
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22. Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease

Author

Darren K. McGuire, Rodica P. Busui, John Deanfield, Silvio E. Inzucchi, Johannes F. E. Mann, Nikolaus Marx, Sharon L. Mulvagh, Neil Poulter, Mads D. M. Engelmann, G. Kees Hovingh, Maria Sejersten Ripa, Mette Gislum, Kirstine Brown‐Frandsen, John B. Buse, Experimental Vascular Medicine, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, and ACS - Amsterdam Cardiovascular Sciences

Subjects
Endocrinology, semaglutide, cardiovascular disease, Endocrinology, Diabetes and Metabolism, Internal Medicine, randomized trial, type 2 diabetes, GLP-1
Abstract

Aim: To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants. Materials and methods: In SOUL, the effects of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double-blind, parallel-group, placebo-controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate

Published
2023

23. Cumulative Systolic Blood Pressure Load and Cardiovascular Risk in Patients With Diabetes

Author

Nelson Wang, Katie Harris, Pavel Hamet, Stephen Harrap, Giuseppe Mancia, Neil Poulter, Bryan Williams, Sophia Zoungas, Mark Woodward, John Chalmers, and Anthony Rodgers

Subjects
Diabetes Mellitus, Type 2, Cardiovascular Diseases, Heart Disease Risk Factors, Risk Factors, Gliclazide, Hypertension, Humans, Blood Pressure, Cardiology and Cardiovascular Medicine
Abstract

Standard measures of blood pressure (BP) do not account for both the magnitude and duration of exposure to elevated BP over time.The purpose of this study was to assess the association between cumulative systolic blood pressure (SBP) load and risk of cardiovascular events in patients with type 2 diabetes.A post hoc analysis of patients with type 2 diabetes followed by the ADVANCE-ON (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation - Observational Study). Cumulative SBP load was defined as the area under curve for SBP values ≥130 mm Hg divided by the area under curve for all measured SBP values over a 24-month exposure period. HRs for the association between cumulative SBP load with major cardiovascular events and death were estimated using Cox models.Over a median 7.6 years of follow-up, 1,469 major cardiovascular events, 1,615 deaths, and 660 cardiovascular deaths were observed in 9,338 participants. Each 1-SD increase in cumulative SBP load was associated with a 14% increase in major cardiovascular events (HR: 1.14; 95% CI: 1.09-1.20), 13% increase in all-cause mortality (HR: 1.13; 95% CI: 1.13-1.18), and 21% increase in cardiovascular death (HR: 1.21; 95% CI: 1.13-1.29). For the prediction of cardiovascular events and death, cumulative SBP load outperformed mean SBP, time-below-target SBP, and visit-to-visit SBP variability in terms of Akaike information criterion and net reclassification indexes.Cumulative SBP load may provide better prediction of major cardiovascular events compared with traditional BP measures among patients with type 2 diabetes. These findings reinforce the importance of both the magnitude and duration of exposure to elevated SBP in assessing cardiovascular risk. (Action in Diabetes and Vascular Disease Preterax and Diamicron MR Controlled Evaluation Post Trial Observational Study [ADVANCE-ON]; NCT00949286).

Published
2022

24. Author response for 'Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: <scp>SOUL</scp> , a randomized trial, design and baseline characteristics'

Author

null Darren K. McGuire, null Rodica P. Busui, null John Deanfield, null Silvio E. Inzucchi, null Johannes F. E. Mann, null Nikolaus Marx, null Sharon L. Mulvagh, null Neil Poulter, null Mads D. M. Engelmann, null G. Kees Hovingh, null Maria Sejersten Ripa, null Mette Gislum, null Kirstine Brown‐Frandsen, and null John B. Buse

Published
2023

25. Ablation versus anti-arrhythmic therapy for reducing all hospital episodes from recurrent atrial fibrillation: a prospective, randomized, multi-centre, open label trial

Author

Prapa Kanagaratnam, James McCready, Muzahir Tayebjee, Ewen Shepherd, Thiagarajah Sasikaran, Derick Todd, Nicholas Johnson, Andreas Kyriacou, Sajad Hayat, Neil A Hobson, Ian Mann, Richard Balasubramaniam, Zachary Whinnett, Mark Earley, Sanjiv Petkar, Rick Veasey, Senthil Kirubakaran, Clare Coyle, Min-Young Kim, Phang Boon Lim, James O’Neill, D Wyn Davies, Nicholas S Peters, Daphne Babalis, Nicholas Linton, Emanuela Falaschetti, Mark Tanner, Jaymin Shah, and Neil Poulter

Subjects
Physiology (medical), Cardiology and Cardiovascular Medicine
Abstract

Aims There is rising healthcare utilization related to the increasing incidence and prevalence of atrial fibrillation (AF) worldwide. Simplifying therapy and reducing hospital episodes would be a valuable development. The efficacy of a streamlined AF ablation approach was compared to drug therapy and a conventional catheter ablation technique for symptom control in paroxysmal AF. Methods and results We recruited 321 patients with symptomatic paroxysmal AF to a prospective randomized, multi-centre, open label trial at 13 UK hospitals. Patients were randomized 1:1:1 to cryo-balloon ablation without electrical mapping with patients discharged same day [Ablation Versus Anti-arrhythmic Therapy for Reducing All Hospital Episodes from Recurrent (AVATAR) protocol]; optimization of drug therapy; or cryo-balloon ablation with confirmation of pulmonary vein isolation and overnight hospitalization. The primary endpoint was time to any hospital episode related to treatment for atrial arrhythmia. Secondary endpoints included complications of treatment and quality-of-life measures. The hazard ratio (HR) for a primary endpoint event occurring when comparing AVATAR protocol arm to drug therapy was 0.156 (95% CI, 0.097–0.250; P < 0.0001 by Cox regression). Twenty-three patients (21%) recorded an endpoint event in the AVATAR arm compared to 76 patients (74%) within the drug therapy arm. Comparing AVATAR and conventional ablation arms resulted in a non-significant HR of 1.173 (95% CI, 0.639–2.154; P = 0.61 by Cox regression) with 23 patients (21%) and 19 patients (18%), respectively, recording primary endpoint events (P = 0.61 by log-rank test). Conclusion The AVATAR protocol was superior to drug therapy for avoiding hospital episodes related to AF treatment, but conventional cryoablation was not superior to the AVATAR protocol. This could have wide-ranging implications on how demand for AF symptom control is met. Trial registration Clinical Trials Registration: NCT02459574.

Published
2022

26. Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials

Author

Christina Reith, Colin Baigent, Lisa Blackwell, Jonathan Emberson, Enti Spata, Kelly Davies, Heather Halls, Lisa Holland, Kate Wilson, Jane Armitage, Charlie Harper, David Preiss, Alistair Roddick, Anthony Keech, John Simes, Rory Collins, Elizabeth Barnes, Jordan Fulcher, William G Herrington, Adrienne Kirby, Borislava Mihaylova, Rachel O'Connell, Pierre Amarenco, Philip Barter, D John Betteridge (deceased), Michael Blazing, Jackie Bosch, Louise Bowman, Eugene Braunwald, Christopher P Cannon, Michael Clearfield, Stuart Cobbe, Helen M Colhoun, Björn Dahlöf, Barry Davis, James de Lemos, John R Downs, Paul N Durrington, Bengt Fellström, Ian Ford, Maria Grazia Franzosi, John Fuller (deceased), Curt Furberg, Robert Glynn, David Gordon, Antonio Gotto Jr, Richard Grimm, Ajay Gupta, C Morton Hawkins, Graham A Hitman, Hallvard Holdaas (deceased), Alan Jardine, J Wouter Jukema, John JP Kastelein, Sharon Kean, John Kjekshus, Genell Knatterud (deceased), Robert H Knopp (deceased), Wolfgang Koenig, Michael Koren, Vera Krane, Martin Landray, John LaRosa, Roberto Latini, Eva Lonn, Donata Lucci, Jean MacFadyen, Peter Macfarlane, Stephen MacMahon, Aldo Maggioni, Roberto Marchioli, Ian Marschner, Lemuel Moyé, Sabina Murphy, Andrew Neil, Enrico B Nicolis, Chris Packard, Sarah Parish, Terje R Pedersen, Richard Peto, Marc Pfeffer, Neil Poulter, Sara Pressel, Jeffrey Probstfield, Mahboob Rahman, Paul M Ridker, Michele Robertson, Frank Sacks, Naveed Sattar, Roland Schmieder, Patrick W Serruys, Peter Sever, John Shaw (deceased), James Shepherd (deceased), Lara Simpson, Peter Sleight (deceased), Luigi Tavazzi, Gianni Tognoni, Andrew Tonkin, Stella Trompet, Christoph Wanner, Hans Wedel, Stephen Weis, K Michael Welch, Harvey White, John Wikstrand, Lars Wilhelmsen, Stephen Wiviott, Robin Young, Salim Yusuf, Faiez Zannad, Hiroyuki Arashi, Robert Byington, Robert Clarke, Marcus Flather, Uri Goldbourt, Shinya Goto, Jemma Hopewell, Kees Hovingh, Patricia Kearney, George Kitas, Connie Newman, Marc S Sabatine, Greg Schwartz, Liam Smeeth, Jonathan Tobert, John Varigos, Junichi Yamaguchi, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, ACS - Pulmonary hypertension & thrombosis, Experimental Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, and Collaboration, Cholesterol Treatment Trialists'

Subjects
Male, Muscles, Australia, Humans, Female, General Medicine, Myalgia, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Middle Aged, Atherosclerosis, Randomized Controlled Trials as Topic
Abstract

Background: Statin therapy is effective for the prevention of atherosclerotic cardiovascular disease and is widely prescribed, but there are persisting concerns that statin therapy might frequently cause muscle pain or weakness. We aimed to address these through an individual participant data meta-analysis of all recorded adverse muscle events in large, long-term, randomised, double-blind trials of statin therapy. Methods: Randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years, and involved a double-blind comparison of statin versus placebo or of a more intensive versus a less intensive statin regimen. We analysed individual participant data from 19 double-blind trials of statin versus placebo (n=123 940) and four double-blind trials of a more intensive versus a less intensive statin regimen (n=30 724). Standard inverse-variance-weighted meta-analyses of the effects on muscle outcomes were conducted according to a prespecified protocol. Findings: Among 19 placebo-controlled trials (mean age 63 years [SD 8], with 34 533 [27·9%] women, 59 610 [48·1%] participants with previous vascular disease, and 22 925 [18·5%] participants with diabetes), during a weighted average median follow-up of 4·3 years, 16 835 (27·1%) allocated statin versus 16 446 (26·6%) allocated placebo reported muscle pain or weakness (rate ratio [RR] 1·03; 95% CI 1·01–1·06). During year 1, statin therapy produced a 7% relative increase in muscle pain or weakness (1·07; 1·04–1·10), corresponding to an absolute excess rate of 11 (6–16) events per 1000 person-years, which indicates that only one in 15 ([1·07–1·00]/1·07) of these muscle-related reports by participants allocated to statin therapy were actually due to the statin. After year 1, there was no significant excess in first reports of muscle pain or weakness (0·99; 0·96–1·02). For all years combined, more intensive statin regimens (ie, 40–80 mg atorvastatin or 20–40 mg rosuvastatin once per day) yielded a higher RR than less intensive or moderate-intensity regimens (1·08 [1·04–1·13] vs 1·03 [1·00–1·05]) compared with placebo, and a small excess was present (1·05 [0·99–1·12]) for more intensive regimens after year 1. There was no clear evidence that the RR differed for different statins, or in different clinical circumstances. Statin therapy yielded a small, clinically insignificant increase in median creatine kinase values of approximately 0·02 times the upper limit of normal. Interpretation: Statin therapy caused a small excess of mostly mild muscle pain. Most (>90%) of all reports of muscle symptoms by participants allocated statin therapy were not due to the statin. The small risks of muscle symptoms are much lower than the known cardiovascular benefits. There is a need to review the clinical management of muscle symptoms in patients taking a statin. Funding: British Heart Foundation, Medical Research Council, Australian National Health and Medical Research Council.

Published
2022

27. Effect of 3, 2-Drug Combinations of Antihypertensive Therapies on Blood Pressure Variability in Black African Patients: Secondary Analyses of the CREOLE Trial

Author

Dike B, Ojji, Victoria, Cornelius, Giles, Partington, Veronica, Francis, Shahiemah, Pandie, Wynand, Smythe, Nicky, Hickman, Felix, Barasa, Albertino, Damasceno, Anastase, Dzudie, Erika, Jones, Prossie Merab, Ingabire, Charles, Mondo, Okechukwu, Ogah, Elijah, Ogola, Mahmoud U, Sani, Gabriel Lamkur, Shedul, Grace, Shedul, Brian, Rayner, Karen, Sliwa, and Neil, Poulter

Subjects
Male, Blood Pressure, Angiotensin-Converting Enzyme Inhibitors, Middle Aged, Blood Pressure Monitoring, Ambulatory, Calcium Channel Blockers, Thiazides, Drug Combinations, Hydrochlorothiazide, Perindopril, Hypertension, Internal Medicine, Humans, Drug Therapy, Combination, Amlodipine, Antihypertensive Agents
Abstract

Background: The effect of 3 commonly recommended combinations of anti-hypertensive agents—amlodipine plus hydrochlorothiazide (calcium channel blocker [CCB]+thiazide), amlodipine plus perindopril (CCB+ACE [angiotensin-converting enzyme]-inhibitor), and perindopril plus hydrochlorothiazide (ACE-inhibitor+thiazide) on blood pressure variability (V) are unknown. Methods: We calculated the blood pressure variability (BPV) in 405 patients (130, 146, and 129 randomized to ACE-inhibitor+thiazide, CCB+thiazide, and CCB+ACE-inhibitor, respectively) who underwent ambulatory blood pressure monitoring after 6 months of treatment in the Comparisons of Three Combinations Therapies in Lowering Blood Pressure in Black Africans trial (CREOLE) of Black African patients. BPV was calculated using the SD of 30-minute interval values for 24-hour ambulatory BPs and for confirmation using the coefficient of variation. Linear mixed model regression was used to calculate mean differences in BPV between treatment arms. Within-clinic BPV was also calculated from the mean SD and coefficient of variation of 3 readings at clinic visits. Results: Baseline distributions of age, sex, and blood pressure parameters were similar across treatment groups. Participants were predominately male (62.2%) with mean age 50.4 years. Those taking CCB+thiazide had significantly reduced ambulatory systolic and diastolic BPV compared with those taking ACE-inhibitor+thiazide. The CCB+thiazide and CCB+ACE-inhibitor groups showed similar BPV. Similar patterns of BPV were apparent among groups using within-clinic blood pressures and when assessed by coefficient of variation. Conclusions: Compared with CCB-containing combinations, ACE-inhibitor plus thiazide was associated with higher levels, generally significant, of ambulatory and within-clinic systolic and diastolic BPV. These results supplement the differential ambulatory blood pressure–lowering effects of these therapies in the CREOLE trial.

Published
2022

30. Bedtime dosing of antihypertensive medications: systematic review and consensus statement: International Society of Hypertension position paper endorsed by World Hypertension League and European Society of Hypertension

Author

George Stergiou, Mattias Brunström, Thomas MacDonald, Konstantinos G. Kyriakoulis, Michael Bursztyn, Nadia Khan, George Bakris, Anastasios Kollias, Ariadni Menti, Paul Muntner, Marcelo Orias, Neil Poulter, Daichi Shimbo, Bryan Williams, Abiodun Moshood Adeoye, Albertino Damasceno, Lyudmila Korostovtseva, Yan Li, Elizabeth Muxfeldt, Yuqing Zhang, Giuseppe Mancia, Reinhold Kreutz, and Maciej Tomaszewski

Subjects
Physiology, Hypertension, Internal Medicine, Humans, Blood Pressure, Prospective Studies, Blood Pressure Monitoring, Ambulatory, Cardiology and Cardiovascular Medicine, Antihypertensive Agents, Circadian Rhythm
Abstract

Antihypertensive drug therapy is one of the most efficient medical interventions for preventing disability and death globally. Most of the evidence supporting its benefits has been derived from outcome trials with morning dosing of medications. Accumulating evidence suggests an adverse prognosis associated with night-time hypertension, nondipping blood pressure (BP) profile and morning BP surge, with increased incidence of cardiovascular events during the first few morning hours. These observations provide justification for complete 24-h BP control as being the primary goal of antihypertensive treatment. Bedtime administration of antihypertensive drugs has also been proposed as a potentially more effective treatment strategy than morning administration. This Position Paper by the International Society of Hypertension reviewed the published evidence on the clinical relevance of the diurnal variation in BP and the timing of antihypertensive drug treatment, aiming to provide consensus recommendations for clinical practice. Eight published outcome hypertension studies involved bedtime dosing of antihypertensive drugs, and all had major methodological and/or other flaws and a high risk of bias in testing the impact of bedtime compared to morning treatment. Three ongoing, well designed, prospective, randomized controlled outcome trials are expected to provide high-quality data on the efficacy and safety of evening or bedtime versus morning drug dosing. Until that information is available, preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice. Complete 24-h control of BP should be targeted using readily available, long-acting antihypertensive medications as monotherapy or combinations administered in a single morning dose.

Published
2022

31. Genome-wide analysis in over 1 million individuals reveals over 2,000 independent genetic signals for blood pressure

Author

Helen Warren, Todd Edwards, Ahmad Vaez, Jacob Keaton, Zoha Kamali, Tian Xie, Alireza Ani, Evangelos Evangelou, Jacklyn Hellwege, Loïc Yengo, William Young, Matthew Traylor, Ayush Giri, Peter Visscher, Daniel Chasman, Andrew Morris, Mark Caulfield, Shih-Jen Hwang, Jaspal Kooner, David Conen, John Attia, Alanna Morrison, Ruth Loos, Kati Kristiansson, Reinhold Schmidt, Andrew Hicks, Peter Pramstaller, Christopher Nelson, Nilesh Samani, Lorenz Risch, Ulf Gyllensten, Olle Melander, Harriëtte Riese, James Wilson, Harry Campbell, Bruce Psaty, Yingchang Lu, Jerome Rotter, Xiuqing Guo, Kenneth Rice, Peter Vollenweider, Johan Sundstrom, Claudia Langenberg, Martin Tobin, Vilmantas Giedraitis, Jian'an Luan, Jaakko Tuomilehto, Zoltan Kutalik, Samuli Ripatti, Veikko Salomaa, Giorgia Girotto, Stella Trompet, J Wouter Jukema, Pim van der Harst, Paul Ridker, Franco Giulianini, Veronique Vitart, Anuj Goel, Hugh Watkins, Sarah Harris, Ian Deary, Peter van der Most, Albertine Oldehinkel, Bernard Keavney, Caroline Hayward, Archie Campbell, Michael Boehnke, Laura Scott, Thibaud Boutin, Chrysovalanto Mamasoula, Marjo-Riitta Jarvelin, Annette Peters, Christian Gieger, Edward Lakatta, Francesco Cucca, Jennie Hui, Paul Knekt, Stefan Enroth, Martin de Borst, Ozren Polasek, Maria Pina Concas, Eulalia Catamo, Massimiliano Cocca, Ruifang Li-Gao, Edith Hofer, Helena Schmidt, Beatrice Spedicati, Melanie Waldenberger, David Strachan, Maris Laan, Alexander Teumer, Marcus Dörr, Vilmundur Gudnason, James Cook, Daniela Ruggiero, Ivana Kolcic, Eric Boerwinkle, Michela Traglia, Terho Lehtimäki, Olli Raitakari, Andrew Johnson, Christopher Newton-Cheh, Morris Brown, Anna Dominiczak, Peter Sever, Neil Poulter, John Chambers, Roberto Elosua, David Siscovick, Tōnu Esko, Andres Metspalu, Rona Strawbridge, Markku Laakso, Anders Hamsten, Jouke-Jan Hottenga, Eco de Geus, Colin Palmer, Ilja Nolte, Yuri Milaneschi, Jonathan Marten, Alan Wright, Eleftheria Zeggini, Joanna Howson, Christopher O'Donnell, Tim Spector, Mike Nalls, Eleanor Simonsick, Yongmei Liu, Cornelia van Duijn, Adam Butterworth, John Danesh, Cristina Menni, Nick Wareham, Kay Khaw, Joshua Denny, Daniel Levy, Patricia Munroe, and Harold Snieder

Abstract

Hypertension is a leading cause of premature death affecting more than a billion individuals worldwide. Here we report on the genetic determinants of blood pressure (BP) traits (systolic, diastolic, and pulse pressure) in the largest single-stage genome-wide analysis to date (N = 1,028,980 European-descent individuals). We identified 2,103 independent genetic signals (P − 8) for BP traits, including 113 novel loci. These associations explain ~ 40% of common SNP heritability of systolic and diastolic BP. Comparison of top versus bottom deciles of polygenic risk scores (PRS) based on these results reveal clinically meaningful differences in BP (12.9 mm Hg for systolic BP, 95% CI 11.5–14.2 mm Hg, p = 9.08×10− 73) and hypertension risk (OR 5.41; 95% CI 4.12 to 7.10; P = 9.71×10− 33) in an independent dataset. Compared with the area under the curve (AUC) for hypertension discrimination for a model with sex, age, BMI, and genetic ancestry, adding systolic and diastolic BP PRS increased discrimination from 0.791 (95% CI = 0.781–0.801) to 0.814 (95% CI = 0.805–0.824, ∆AUC = 0.023, P = 2.27x10− 22). Our transcriptome-wide association study detected 2,793 BP colocalized associations with genetically-predicted expression of 1,070 genes in five cardiovascular tissues, of which 500 are previously unreported for BP traits. These findings represent an advance in our understanding of hypertension and highlight the role of increasingly large genomic studies for development of more accurate PRS, which may inform precision health research.

Published
2022

32. Yoga-Based Cardiac Rehabilitation After Acute Myocardial Infarction

Author

Dorairaj Prabhakaran, Ambalam M. Chandrasekaran, Kalpana Singh, Bishav Mohan, Kaushik Chattopadhyay, Davinder S. Chadha, Prakash C. Negi, Prabhavathi Bhat, Kanchanahalli S. Sadananda, Vamadevan S. Ajay, Kavita Singh, Pradeep A. Praveen, Raji Devarajan, Dimple Kondal, Divya Soni, Poppy Mallinson, Subhash C. Manchanda, Kushal Madan, Alun D. Hughes, Nishi Chathurvedi, Ian Roberts, Shah Ebrahim, Kolli S. Reddy, Nikhil Tandon, Stuart Pocock, Ambuj Roy, Sanjay Kinra, Subhash Chand Manchanda, Ajay Vamadevan S, Kolli Srinath Reddy, Deepak Bhatnagar, Vivek Chaturvedi, Pablo Perel, Neil Poulter, S. Harikrishnan, Ravindra M. Pandey, Amitava Banerjee, Paramjit Gill, Davinder Singh Chadha, Neil Bardoloi, Prakash Chand Negi, Sanjeev Asotra, Prabhavati Bhat, Manjunath C. Nanjappa, M.R. Prasad, Raghava Sarma, K.U. Natrajan, Srikumar Swaminathan, Ravindra K. Tongia, S. Natarajan, Bhaskara Rao, Calambur Narasimhan, Jabir Abdullakutty, Srinivas Mallya, Anil R. Jain, Sudhir R. Naik, Nagraj Desai, Sunil Kumar, Shankar Patil, Satish Patil, Sharad Chandra, and Nagamalesh U. Madappa

Subjects
Adult, Male, medicine.medical_specialty, Visual analogue scale, medicine.medical_treatment, Myocardial Infarction, India, acute myocardial infarction, 030204 cardiovascular system & hematology, Article, law.invention, rehabilitation, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, medicine, Humans, 030212 general & internal medicine, Myocardial infarction, Stroke, Exercise, Rehabilitation, Cardiac Rehabilitation, business.industry, EQ-5D-5L, European Quality of Life–5 Dimensions–5 Level, Yoga, Hazard ratio, Middle Aged, medicine.disease, humanities, Emergency medicine, Patient Compliance, Female, Cardiology and Cardiovascular Medicine, business, Yoga-CaRe, yoga-based cardiac rehabilitation, Mace, coronary artery disease, secondary prevention
Abstract

Background Given the shortage of cardiac rehabilitation (CR) programs in India and poor uptake worldwide, there is an urgent need to find alternative models of CR that are inexpensive and may offer choice to subgroups with poor uptake (e.g., women and elderly). Objectives This study sought to evaluate the effects of yoga-based CR (Yoga-CaRe) on major cardiovascular events and self-rated health in a multicenter randomized controlled trial. Methods The trial was conducted in 24 medical centers across India. This study recruited 3,959 patients with acute myocardial infarction with a median and minimum follow-up of 22 and 6 months. Patients were individually randomized to receive either a Yoga-CaRe program (n = 1,970) or enhanced standard care involving educational advice (n = 1,989). The co-primary outcomes were: 1) first occurrence of major adverse cardiovascular events (MACE) (composite of all-cause mortality, myocardial infarction, stroke, or emergency cardiovascular hospitalization); and 2) self-rated health on the European Quality of Life–5 Dimensions–5 Level visual analogue scale at 12 weeks. Results MACE occurred in 131 (6.7%) patients in the Yoga-CaRe group and 146 (7.4%) patients in the enhanced standard care group (hazard ratio with Yoga-CaRe: 0.90; 95% confidence interval [CI]: 0.71 to 1.15; p = 0.41). Self-rated health was 77 in Yoga-CaRe and 75.7 in the enhanced standard care group (baseline-adjusted mean difference in favor of Yoga-CaRe: 1.5; 95% CI: 0.5 to 2.5; p = 0.002). The Yoga-CaRe group had greater return to pre-infarct activities, but there was no difference in tobacco cessation or medication adherence between the treatment groups (secondary outcomes). Conclusions Yoga-CaRe improved self-rated health and return to pre-infarct activities after acute myocardial infarction, but the trial lacked statistical power to show a difference in MACE. Yoga-CaRe may be an option when conventional CR is unavailable or unacceptable to individuals. (A study on effectiveness of YOGA based cardiac rehabilitation programme in India and United Kingdom; CTRI/2012/02/002408)., Central Illustration

Published
2020

34. May Measurement Month 2018: an analysis of blood pressure screening results from Botswana

Author

Xin Xia, Tiny Masupe, Thomas Beaney, Mary Banyana Tiro, Anca Chis Ster, Neil Poulter, Onalethata Lesetedi, Masego Kololo, Mosepele Mosepele, Orapeleng Phuswane, Obuile Makwati, John Thato Tlhakanelo, Amogelang Motlhagodi, Abraham Mamela, and Keneilwe Motlhatlhedi

Subjects
Physiology, Cardiovascular risk factors, 030204 cardiovascular system & hematology, Unit of alcohol, 03 medical and health sciences, 0302 clinical medicine, Control, Internal Medicine, medicine, AcademicSubjects/MED00200, 030212 general & internal medicine, Risk factor, 1102 Cardiorespiratory Medicine and Haematology, Volunteer, business.industry, Mean age, Articles, medicine.disease, Obesity, Treatment, Blood pressure, Cardiovascular System & Hematology, Hypertension, Capital city, Screening, Cardiology and Cardiovascular Medicine, business, Demography
Abstract

During the May Measurement Month 2018 (MMM18) campaign, we aimed to raise hypertension awareness and measure blood pressure (BP) across different communities in Botswana. Study sites included four large villages and Gaborone (capital city). Screening sites were shopping malls, train stations, churches, and workplaces. Individuals aged ≥18 years were recruited through fliers, word of mouth, and as volunteer walk-ins at the sites. Demographic and risk factor data were collected through a questionnaire prior to measuring three BP readings per participant. Weight was measured while height was usually estimated. Hypertension was defined as: systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg or taking antihypertensive medication. The mean of readings 2 and 3 was used and was estimated using multiple imputation where missing. Amongst 4599 participants whose BPs were measured, 54.5% were female, while mean age was 35.9 years. A total of 1510 (32.8%) participants were hypertensive and of those, 712 (47.1%) were aware of the hypertension. Only 35.2% of hypertensives were on antihypertensive treatment with 54.4% had controlled BP. Amongst all hypertensives, only 19.1% had controlled BP. Risk factors associated with higher BP included obesity, more than 1 unit of alcohol/week and BP measured on Sunday. Less than half (47.1%) of those identified as having hypertension during MMM18 were aware of their condition, despite the escalating prevalence of hypertension in the country. Regular BP awareness and opportunistic BP measurement campaigns like MMM are recommended to improve detection and control of hypertension and other cardiovascular risk factors.

Published
2020

35. Ablation versus Anti-Arrhythmic Therapy for Reducing All Hospital Episodes from Recurrent Atrial Fibrillation (AVATAR-AF): Design and rationale

Author

I Mann, Ewen Shepherd, Nicholas Johnson, Prapa Kanagaratnam, Derick Todd, F Neil Poulter, Thiagarajah Sasikaran, Belinda Sandler, Emanuela Falaschetti, Daphne Babalis, Andrew Copley, Muzahir H. Tayebjee, James McCready, Medtronic International Trading Sarl, and British Heart Foundation

Subjects
medicine.medical_specialty, medicine.medical_treatment, Recurrent atrial fibrillation, 030204 cardiovascular system & hematology, Cryosurgery, 1117 Public Health and Health Services, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Recurrence, law, Atrial Fibrillation, Clinical endpoint, Humans, Multicenter Studies as Topic, Medicine, Anti arrhythmic, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, 1102 Cardiorespiratory Medicine and Haematology, Randomized Controlled Trials as Topic, Cross-Over Studies, business.industry, Atrial fibrillation, Ablation, medicine.disease, Crossover study, Electrophysiological Phenomena, Hospitalization, Treatment Outcome, Ambulatory Surgical Procedures, Cardiovascular System & Hematology, Pulmonary Veins, Emergency medicine, Catheter Ablation, Symptom Assessment, Cardiology and Cardiovascular Medicine, business, Anti-Arrhythmia Agents
Abstract

Atrial Fibrillation (AF) ablation using the cryoballoon is effective at reducing symptomatic AF episodes. The prevalence of AF is increasing with the aging population and access to such treatment would be enhanced by reducing the resource requirements. Relinquishing electrical mapping of the pulmonary veins (PV) removes the need for PV catheters, electrical recording equipment and staff trained in using this equipment. Moreover, the majority of complications are peri-procedural so overnight hospitalization maybe unnecessary. We tested this streamlined approach to AF ablation against medical therapy using the endpoint of time to all hospital episodes. METHODS: The AVATAR-AF study is a prospective, multicenter, randomized controlled trial testing the primary hypothesis that AF ablation done without PV mapping or overnight hospitalization is more effective than anti-arrhythmic drugs at reducing all hospital episodes related to recurrent atrial arrhythmias. We included a third arm to test a secondary hypothesis that confirming PV entrance block as per consensus guidelines can improve outcomes. Three hundred twenty-one patients with documented paroxysmal AF will be randomized in a 1:1:1 manner to one of three investigation arms: (1) AVATAR protocol cryoballoon ablation without assessment of acute PV isolation or overnight hospitalization; (2) medical therapy with anti-arrhythmic drugs; or (3) conventional cryoballoon ablation with assessment of acute PV isolation. The primary endpoint is defined as the time to all hospital episodes (including outpatient consultation) related to treatment for atrial arrhythmia. CONCLUSION: The AVATAR-AF study will determine whether the resource utilization for AF ablation can be reduced whilst maintaining superiority over medical therapy.

Published
2019

36. Comparison of Dual Therapies for Lowering Blood Pressure in Black Africans

Author

Dike B, Ojji, Bongani, Mayosi, Veronica, Francis, Motasim, Badri, Victoria, Cornelius, Wynand, Smythe, Nicky, Kramer, Felix, Barasa, Albertino, Damasceno, Anastase, Dzudie, Erika, Jones, Charles, Mondo, Okechukwu, Ogah, Elijah, Ogola, Mahmoud U, Sani, Gabriel L, Shedul, Grace, Shedul, Brian, Rayner, Ikechi G, Okpechi, Karen, Sliwa, Neil, Poulter, and K, Sliwa

Subjects
Male, RATIONALE, Blood Pressure, 030204 cardiovascular system & hematology, law.invention, 0302 clinical medicine, Hydrochlorothiazide, Randomized controlled trial, law, Perindopril, Single-Blind Method, 030212 general & internal medicine, 11 Medical and Health Sciences, African Continental Ancestry Group, OUTCOMES, General Medicine, Middle Aged, EUROPEAN-SOCIETY, Drug Combinations, TRIALS, CREOLE Study Investigators, Hypertension, Drug Therapy, Combination, Female, Life Sciences & Biomedicine, medicine.drug, Adult, medicine.medical_specialty, Black african, Black People, 03 medical and health sciences, Medicine, General & Internal, Pharmacotherapy, General & Internal Medicine, Internal medicine, HYDROCHLOROTHIAZIDE, MANAGEMENT, medicine, Humans, Amlodipine, CARDIOVASCULAR EVENTS, Africa South of the Sahara, Antihypertensive Agents, Aged, Science & Technology, AMLODIPINE, business.industry, EFFICACY, Logistic Models, Blood pressure, Multicenter study, ARTERIAL-HYPERTENSION, business
Abstract

BACKGROUND The prevalence of hypertension among black African patients is high, and these patients usually need two or more medications for blood-pressure control. However, the most effective two-drug combination that is currently available for blood-pressure control in these patients has not been established. METHODS In this randomized, single-blind, three-group trial conducted in six countries in sub-Saharan Africa, we randomly assigned 728 black patients with uncontrolled hypertension (≥140/90 mm Hg while the patient was not being treated or was taking only one antihypertensive drug) to receive a daily regimen of 5 mg of amlodipine plus 12.5 mg of hydrochlorothiazide, 5 mg of amlodipine plus 4 mg of perindopril, or 4 mg of perindopril plus 12.5 mg of hydrochlorothiazide for 2 months. Doses were then doubled (10 and 25 mg, 10 and 8 mg, and 8 and 25 mg, respectively) for an additional 4 months. The primary end point was the change in the 24-hour ambulatory systolic blood pressure between baseline and 6 months. RESULTS The mean age of the patients was 51 years, and 63% were women. Among the 621 patients who underwent 24-hour blood-pressure monitoring at baseline and at 6 months, those receiving amlodipine plus hydrochlorothiazide and those receiving amlodipine plus perindopril had a lower 24-hour ambulatory systolic blood pressure than those receiving perindopril plus hydrochlorothiazide (between-group difference in the change from baseline, −3.14 mm Hg; 95% confidence interval [CI], −5.90 to −0.38; P=0.03; and −3.00 mm Hg; 95% CI, −5.8 to −0.20; P=0.04, respectively). The difference between the group receiving amlodipine plus hydrochlorothiazide and the group receiving amlodipine plus perindopril was −0.14 mm Hg (95% CI, −2.90 to 2.61; P=0.92). Similar differential effects on office and ambulatory diastolic blood pressures, along with blood-pressure control and response rates, were apparent among the three groups. CONCLUSIONS These findings suggest that in black patients in sub-Saharan Africa, amlodipine plus either hydrochlorothiazide or perindopril was more effective than perindopril plus hydrochlorothiazide at lowering blood pressure at 6 months. (Funded by GlaxoSmithKline Africa Noncommunicable Disease Open Lab; CREOLE ClinicalTrials.gov number, NCT02742467. opens in new tab.)

Published
2019

37. Fixed‐ratio combination of insulin degludec and liraglutide (IDegLira) improves cardiovascular risk markers in patients with type 2 diabetes uncontrolled on basal insulin

Author

Lawrence A. Leiter, Lucine Lehmann, Nikolaos Tentolouris, Neil Poulter, Esteban Jódar, Thomas Blevins, Tina Vilsbøll, and Bue F. Ross Agner

Subjects
Male, Insulin degludec, Endocrinology, Diabetes and Metabolism, Enfermedad cardiovascular, Blood Pressure, Type 2 diabetes, 030204 cardiovascular system & hematology, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, cardiovascular disease, Risk Factors, Insulina Glargina, liraglutide, Brief Report, Middle Aged, Insulin, Long-Acting, Drug Combinations, Diabetes mellitus tipo 2, Cardiovascular Diseases, Female, type 2 diabetes, Factores de riesgo de enfermedad cardiaca, Waist Circumference, medicine.drug, medicine.medical_specialty, Urology, 030209 endocrinology & metabolism, Endocrinology & Metabolism, 03 medical and health sciences, Diabetes mellitus, Post-hoc analysis, Internal Medicine, medicine, Humans, Hypoglycemic Agents, basal insulin, Aged, Cholesterol, business.industry, Insulin glargine, Liraglutide, 1103 Clinical Sciences, medicine.disease, Blood pressure, Diabetes Mellitus, Type 2, chemistry, Brief Reports, business
Abstract

In this post hoc analysis we investigated the effects of insulin degludec/liraglutide fixed-ratio combination (IDegLira) versus comparators on cardiovascular (CV) risk markers in participants in the DUAL II (vs. insulin degludec), DUAL V (vs. insulin glargine 100 units/mL) and DUAL VII (vs. basal-bolus therapy) trials, grouped by sex, age (

Published
2019

38. Efficacy and Safety of Incremental Dosing of a New Single-Pill Formulation of Perindopril and Amlodipine in the Management of Hypertension

Author

Eoin O'Brien, Neil Poulter, Peter S. Sever, Andrew J. O. Whitehouse, Ajay Gupta, and Eamon Dolan

Subjects
Male, Cardiac & Cardiovascular Systems, ENGLAND, Angiotensin-Converting Enzyme Inhibitors, Blood Pressure, BLOOD-PRESSURE, 030204 cardiovascular system & hematology, GUIDELINES, Severity of Illness Index, law.invention, 0302 clinical medicine, Hydrochlorothiazide, Randomized controlled trial, law, Perindopril, Clinical endpoint, Pharmacology (medical), Pharmacology & Pharmacy, 030212 general & internal medicine, 1102 Cardiorespiratory Medicine and Haematology, OUTCOMES, General Medicine, Middle Aged, Calcium Channel Blockers, Drug Combinations, VARIABILITY, Hypertension, Ambulatory, Cardiology, Female, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, medicine.drug, medicine.medical_specialty, SOCIETY, 03 medical and health sciences, Irbesartan, Double-Blind Method, Internal medicine, HYDROCHLOROTHIAZIDE, medicine, Humans, Amlodipine, Antihypertensive Agents, Aged, Science & Technology, Dose-Response Relationship, Drug, business.industry, PREVENTION, FIXED COMBINATION, HIGH-RISK, Blood pressure, Cardiovascular System & Hematology, Cardiovascular System & Cardiology, business
Abstract

BACKGROUND: Angiotensin-converting enzyme inhibitors and calcium channel blockers in combination are widely recommended in hypertension guidelines. The advantages of single-pill combinations (SPCs) are increasingly recognized, so a dosage-adapted combination of perindopril and amlodipine was developed for the initial management of hypertension. OBJECTIVE: This randomized trial evaluated the blood pressure (BP)-lowering efficacy of four incremental doses of perindopril/amlodipine SPC in adults with mild-to-severe hypertension. METHODS: Eligible patients (N = 1617) were randomized to SPC perindopril 3.5 mg/amlodipine 2.5 mg (i.e., 3.5/2.5 mg) daily, uptitrating as required on a monthly basis up to 14/10 mg until BP

Published
2019

39. History of lower-limb complications and risk of cancer death in people with type 2 diabetes

Author

Mark Woodward, Giuseppe Mancia, Kamel Mohammedi, Michel Marre, John Chalmers, Stephen Harrap, Neil Poulter, Gestionnaire, Hal Sorbonne Université, CHU Bordeaux [Bordeaux], Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Melbourne, Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Imperial College London, University of New South Wales [Sydney] (UNSW), Johns Hopkins University (JHU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), and Admin, Oskar

Subjects
Male, lcsh:Diseases of the circulatory (Cardiovascular) system, Time Factors, Cardiac & Cardiovascular Systems, Peripheral neuropathy, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Type 2 diabetes, 030204 cardiovascular system & hematology, MELLITUS, 0302 clinical medicine, Risk Factors, Neoplasms, Cancer death, article clinique, 1102 Cardiorespiratory Medicine and Haematology, Randomized Controlled Trials as Topic, Original Investigation, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, education.field_of_study, OUTCOMES, CARDIOVASCULAR HEALTH, Incidence, Hazard ratio, Absolute risk reduction, Peripheral Nervous System Diseases, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 16. Peace & justice, Prognosis, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV] Life Sciences [q-bio], Lower Extremity, Lower-limb complication, Female, Cardiology and Cardiovascular Medicine, Risk assessment, Cancers, BURDEN, Life Sciences & Biomedicine, medicine.medical_specialty, Population, 030209 endocrinology & metabolism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Risk Assessment, 03 medical and health sciences, Endocrinology & Metabolism, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Diabetes mellitus, Internal medicine, Peripheral arterial disease, medicine, Humans, education, Aged, Science & Technology, Proportional hazards model, business.industry, PERIPHERAL ARTERIAL-DISEASE, MORTALITY, medicine.disease, Diabetes Mellitus, Type 2, Cardiovascular System & Hematology, lcsh:RC666-701, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cardiovascular System & Cardiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

Background Individuals with diabetes and lower-limb complications are at high risk for cardiovascular and all-cause mortality, but uncertainties remain in terms of cancer-related death in this population. We investigated this relationship in a large cohort of people with type 2 diabetes. Methods We used data from the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) study. The primary outcome was adjudicated cancer death; secondary outcomes were overall and site-specific incident cancers, determined according to the International Classification of Diseases Code (ICD-10). We compared outcomes in individuals with (versus without) a baseline history of lower-limb complications (peripheral artery disease (PAD) or sensory peripheral neuropathy) using Cox regression models. Results Among 11,140 participants (women 42%, mean age 66 years), lower-limb complications were reported at baseline in 4293 (38%) individuals: 2439 (22%) with PAD and 2973 (27%) with peripheral neuropathy. Cancer death occurred in 316 (2.8%) participants during a median of 5.0 (25th–75th percentile, 4.7–5.1) years of follow-up corresponding to 53,550 person-years and an incidence rate of 5.9 (95% CI 5.3–6.6) per 1000 person-years. The risk of cancer death was higher in individuals with (versus without) lower-limb complication [hazard ratio 1.53 (95% CI, 1.21–1.94), p = 0.0004], PAD [1.32 (1.02–1.70), p = 0.03] or neuropathy (1.41 (1.11–1.79), p = 0.004], adjusting for potential confounders and study allocations. PAD, but not neuropathy, was associated with excess risk of incident cancers. Conclusions PAD and peripheral neuropathy were independently associated with increased 5-year risk of cancer death in individuals with type 2 diabetes. PAD was also associated with increased risk of incident cancers. Our findings provide new evidence on the non-cardiovascular prognostic burden of lower-limb complications in people with type 2 diabetes.

Published
2020

40. 2020 International Society of Hypertension global hypertension practice guidelines

Author

Dorairaj Prabhakaran, Neil Poulter, Nadia A. Khan, Maciej Tomaszewski, Bryan Williams, Claudio Borghi, Fadi J. Charchar, Agustin J. Ramirez, George S. Stergiou, Aletta E. Schutte, Markus P. Schlaich, Richard D Wainford, Thomas Unger, RS: CARIM other, 10922180 - Schutte, Aletta Elisabeth, Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, Ramirez A, Schlaich M, Stergiou GS, Tomaszewski M, Wainford RD, Williams B, Schutte AE, and Thomas Unger , Claudio Borghi , Fadi Charchar , Nadia A Khan , Neil R Poulter , Dorairaj Prabhakaran , Agustin Ramirez , Markus Schlaich , George S Stergiou , Maciej Tomaszewsk , Richard D Wainford , Bryan Williams , Aletta E Schutte

Subjects
Physiology, Resistant hypertension, Global Health, RESISTANT HYPERTENSION, ETHNIC-DIFFERENCES, MASKED HYPERTENSION, Global health, Medicine, 1102 Cardiorespiratory Medicine and Haematology, Hypertension treatment, HIGH BLOOD-PRESSURE, Standard of Care, EUROPEAN-SOCIETY, Clinical Practice, hypertension diagnosis, CARDIOVASCULAR-DISEASE, Evidence-Based Practice, Drug Therapy, Combination, Cardiology and Cardiovascular Medicine, Hypertension, Guidelines, medicine.medical_specialty, Evidence-based practice, hypertension, Medication Therapy Management, MEDLINE, Medication adherence, Pharmacotherapy, Medication therapy management, hypertension treatment, Internal Medicine, SYSTEMATIC ANALYSIS, TO-HEIGHT RATIO, Humans, Hypertension diagnosis, MEDICATION ADHERENCE, hypertension guidelines, Intensive care medicine, Antihypertensive Agents, business.industry, Blood Pressure Determination, 1103 Clinical Sciences, HOME BLOOD-PRESSURE, Masked Hypertension, Cardiovascular System & Hematology, Heart Disease Risk Factors, CLINICAL-PRACTICE, 1116 Medical Physiology, RISK-FACTORS, ARTERIAL-HYPERTENSION, Hypertension, blood pressure, guidelines, Combination method, business, Risk Reduction Behavior
Abstract

Statement of remit: To align with its mission to reduce the global burden of raised blood pressure (BP), the International Society of Hypertension (ISH) has developed worldwide practice guidelines for the management of hypertension in adults, aged 18 years and older. The ISH Guidelines Committee extracted evidence-based content presented in recently published extensively reviewed guidelines and tailored ESSENTIAL and OPTIMAL standards of care in a practical format that is easy-to-use particularly not only in low-resource settings but also in high-resource settings- by clinicians, but also nurses and community health workers, as appropriate. Although distinction between low-resource and high-resource settings often refers to high (HIC) and low-income and middle-income countries (LMIC), it is well established that in HIC, there are areas with low-resource settings, and vice versa. Herein optimal care refers to evidence-based standard-of-care articulated in recent guidelines [1,2] and summarized here, whereas essential standards recognize that optimal standards would not always be possible. Hence, essential standards refer to minimum standards of care. To allow specification of essential standards of care for low-resource settings, the Committee was often confronted with the limitation or absence in clinical evidence, and thus applied expert opinion. In the Guidelines, differentiation between optimal and essential standards were not always possible, and were made in sections where it was most practical and sensible. The Guidelines Committee is also aware that some recommended essential standards may not be feasible in low-resource settings, for example, out-of-office BP measurements, the requirement of multiple visits for the diagnosis of hypertension, or advising the use of single pill combination therapy. Although challenging to implement, these guidelines may aid in local initiatives to motivate policy changes and serve as an instrument to drive local improvements in standards of care. Every effort should be made to achieve essential standards of care to reduce hypertension-induced cardiovascular morbidity and mortality.

Published
2020

42. Type 2 Diabetes and the Reduction of Cardiovascular Risk: Sorting Out the Actors and the Roles

Author

Robert A. Hegele, Ross D. Feldman, David Fitchett, and Neil Poulter

Subjects
Type 2 diabetes, 030204 cardiovascular system & hematology, Bioinformatics, 1102 Cardiovascular Medicine And Haematology, Risk Assessment, Reduction (complexity), 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, medicine, Humans, Hypoglycemic Agents, 030212 general & internal medicine, Age of Onset, business.industry, Blood Glucose Self-Monitoring, Sorting, Prognosis, medicine.disease, Causality, Cardiovascular System & Hematology, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Disease Progression, Cardiology and Cardiovascular Medicine, business, Risk Reduction Behavior, Dyslipidemia
Published
2018

43. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase

Author

Rory Collins, Timothy Collier, David Thompson, Peter S. Sever, Ajay Gupta, Neil Poulter, Andrew J. O. Whitehouse, Björn Dahlöf, Pfizer Limited, Imperial College Trust, Foundation for Circulatory Health, and National Institute for Health Research

Subjects
Male, Atorvastatin, MedDRA, Placebo-controlled study, 030204 cardiovascular system & hematology, 0302 clinical medicine, Risk Factors, PARTICIPANTS, 030212 general & internal medicine, Myocardial infarction, Nocebo Effect, 11 Medical and Health Sciences, Hypolipidemic Agents, RISK, Hazard ratio, General Medicine, Middle Aged, Treatment Outcome, CARDIOVASCULAR-DISEASE, Early Termination of Clinical Trials, Hypertension, Female, Lipid lowering, Statin therapy, Life Sciences & Biomedicine, CLINICAL-TRIALS, medicine.drug, Adult, Sleep Wake Disorders, medicine.medical_specialty, Statin, medicine.drug_class, INTOLERANCE, Hypercholesterolemia, Placebo, ASCOT Investigators, Double blind, 03 medical and health sciences, Medicine, General & Internal, Double-Blind Method, Muscular Diseases, General & Internal Medicine, Internal medicine, MANAGEMENT, medicine, Humans, Adverse effect, Lymphatic Diseases, Aged, Science & Technology, business.industry, medicine.disease, PREVENTION, Hematologic Diseases, Surgery, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business
Abstract

Summary Background In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials. Methods In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40–79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest—muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment—and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum. Results The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3·3 years (IQR 2·7–3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] non-users), with a median follow-up of 2·3 years (2·2–2·4). During the blinded phase, muscle-related AEs (298 [2·03% per annum] vs 283 [2·00% per annum]; hazard ratio 1·03 [95% CI 0·88–1·21]; p=0·72) and erectile dysfunction (272 [1·86% per annum] vs 302 [2·14% per annum]; 0·88 [0·75–1·04]; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1·00% per annum] vs 210 [1·46% per annum]; 0·69 [0·56–0·85]; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0·20% per annum] vs 32 [0·22% per annum]; 0·94 [0·57–1·54]; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1·87%] per annum vs 392 [1·51%] per annum; 1·23 [1·08–1·41]; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10–1·79]; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8·69% per annum] vs 831 [7·45% per annum]; 1·17 [1·06–1·29]; p=0·001) and blood and lymphatic system disorders (114 [0·88% per annum] vs 80 [0·64% per annum]; 1·40 [1·04–1·88]; p=0·03), which were reported more commonly by statin users than by non-users. Interpretation These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects. Funding Pfizer, Servier Research Group, and Leo Laboratories.

Published
2017

44. Baseline characteristics of patients enrolled in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL)

Author

M. Angelyn Bethel, Adrian F. Hernandez, Ambady Ramachandran, Peter Öhman, John B. Buse, Stephanie M. Gustavson, Robert J. Mentz, Nayyar Iqbal, Juliana C.N. Chan, Aldo P. Maggioni, Neil Poulter, Bernard Zinman, Vivian P. Thompson, Rury R. Holman, Steven P. Marso, and Neha J. Pagidipati

Subjects
Male, medicine.medical_specialty, Myocardial Infarction, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Placebo, Article, Glucagon-Like Peptide-1 Receptor, law.invention, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, Risk Factors, law, Diabetes mellitus, Internal medicine, medicine, Humans, Hypoglycemic Agents, Myocardial infarction, Aged, Venoms, business.industry, Middle Aged, medicine.disease, Surgery, Stroke, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Heart failure, Exenatide, Female, Peptides, Cardiology and Cardiovascular Medicine, business, Mace, medicine.drug
Abstract

Background EXSCEL is a randomized, double-blind, placebo-controlled trial examining the effect of exenatide once-weekly (EQW) versus placebo on time to the primary composite outcome (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) in patients with type 2 diabetes mellitus (DM) and a wide range of cardiovascular (CV) risk. Methods Patients were enrolled at 688 sites in 35 countries. We describe their baseline characteristics according to prior CV event status and compare patients with those enrolled in prior glucagon-like peptide-1 receptor agonist (GLP-1RA) outcomes trials. Results Of a total of 14,752 participants randomized between June 2010 and September 2015, 6,788 (46.0%) patients were enrolled in Europe; 3,708 (25.1%), North America; 2,727 (18.5%), Latin America; and 1,529 (10.4%), Asia Pacific. Overall, 73% had at least one prior CV event (70% coronary artery disease, 24% peripheral arterial disease, 22% cerebrovascular disease). The median (IQR) age was 63 years (56, 69), 38% were female, median baseline HbA1c was 8.0% (7.3, 8.9) and 16% had a prior history of heart failure. Those without a prior CV event were younger with a shorter duration of diabetes and better renal function than those with at least one prior CV event. Compared with prior GLP-1RA trials, EXSCEL has a larger percentage of patients without a prior CV event and a notable percentage who were taking a dipeptidyl peptidase-4 inhibitor at baseline (15%). Conclusions EXSCEL is one of the largest global GLP-1RA trials, evaluating the safety and efficacy of EQW with a broad patient population that may extend generalizability compared to prior GLP-1RA trials (ClinicalTrials.gov number, NCT01144338).

Published
2017

45. Associations of autozygosity with a broad range of human phenotypes

Author

Dennis O. Mook-Kanamori, Salma M. Wakil, Lisa R. Yanek, Dominique P.V. de Kleijn, Gert J. de Borst, Alison D. Murray, Kamran Guity, Vincent W. V. Jaddoe, Mario Pirastu, Carole Ober, Giuseppe Matullo, Charles N. Rotimi, Daniela Ruggiero, Teresa Tusié-Luna, Wolfgang Lieb, Chew-Kiat Heng, John R. B. Perry, Hortensia Moreno-Macías, Jie Zhou, John M. Starr, Juhani Junttila, Lei Yu, Danielle Posthuma, Marcus Dörr, Yingchang Lu, Jonathan P. Bradfield, Einat Granot-Hershkovitz, Karina Meidtner, Wouter van Rheenen, T Esko, Maris Alver, Wen-Jane Lee, Zhengming Chen, Jennifer A. Brody, Paolo Gasparini, Yii-Der Ida Chen, Cinzia Sala, Peter P. Pramstaller, Gauri Prasad, Nana Matoba, Natalie Terzikhan, Simonetta Guarrera, Bjarke Feenstra, Peter Vollenweider, Smeeta Shrestha, Yi-Jen Hung, Lilja Stefansdottir, David R. Weir, Felix R. Day, Antonietta Robino, Liang Zhang, Lluis Quintana-Murci, Nicholas J. Timpson, Robyn E Wootton, Xue W. Mei, Dharambir K. Sanghera, Gisli Masson, Debbie A Lawlor, Thomas Meitinger, Sharon L.R. Kardia, Peter K. Joshi, Frank J. A. van Rooij, Claude Bouchard, Cassandra N. Spracklen, Ken K. Ong, Taulant Muka, Guanjie Chen, Laura J. Scott, Walter Palmas, Daniel I. Chasman, Sarah E. Medland, Krista Fischer, Blair H. Smith, Jon K. Sigurdsson, Leon Straker, Clara Viberti, Yuan Shi, Louis Pérusse, Peter J. van der Most, Timo Tõnis Sikka, Chris Haley, Kuang Lin, Leif Groop, Hester M. den Ruijter, Hakon Hakonarson, Masato Akiyama, Stephan J. L. Bakker, Sonja I. Berndt, Jeffery R. O'Connell, Cisca Wijmenga, Daniele Cusi, Lorena Orozco, Kristjan H. S. Moore, Kevin Sandow, Stephen S. Rich, Stephanie J. Loomis, George Davey Smith, Cornelia M. van Duijn, Sharvari Rahul Shukla, Agnar Helgason, Thorsten Kessler, Anuj Goel, Dan Mason, David W. Clark, James S. Pankow, Simona Vaccargiu, Uwe Völker, Tamara B. Harris, Matthew A. Allison, Clicerio Gonzalez, Sarju Ralhan, I-Te Lee, Matthias Laudes, Yen-Feng Chiu, Neil Poulter, Benjamin Lehne, John Wright, Lawrence F. Bielak, Philip L. De Jager, Reinhold Schmidt, Ya Xing Wang, Matthias Nauck, Diana L. Cousminer, Patrick Deelen, Ani Manichaikul, Stephen J. Chanock, Anders Hamsten, Barry I. Freedman, Gudmar Thorleifsson, Peter Kraft, Ozren Polasek, Jie Yao, Yoshinori Murakami, Paul M. Ridker, Anubha Mahajan, Struan F.A. Grant, Claudia Schurmann, Bjarni Gunnarsson, Catriona L. K. Barnes, Jessica van Setten, Sandosh Padmanabhan, Alena Stančáková, Markus M. Lerch, Anuradha Jagadeesan, Franco Giulianini, Daniel F. Gudbjartsson, Dwaipayan Bharadwaj, Shengchao Alfred Li, Peter S. Sever, Trevor A. Mori, Albertine J. Oldehinkel, Koichi Matsuda, Xueling Sim, Evangelos Evangelou, André G. Uitterlinden, Pekka Jousilahti, Yukihide Momozawa, Ioanna Tzoulaki, Chao A. Hsiung, Ginevra Biino, Murielle Bochud, Hannele Mattsson, Ilja M. Nolte, Sarah H. Wild, Patricia B. Munroe, Jianjun Liu, Bruce M. Psaty, Giriraj R. Chandak, Masahiro Kanai, Tony R. Merriman, Teemu Palviainen, Rodney A. Lea, Janie Corley, Nicholas J. Wareham, Alan B. Zonderman, Makoto Hirata, Matthew J. Bixley, Caroline Hayward, Nora Franceschini, Kristel R van Eijk, Etienne Patin, Daniel Shriner, Niek Verweij, Xiuqing Guo, Fredrik Karpe, Ruth J. F. Loos, Tiinamaija Tuomi, Ashley van der Spek, Patricia A. Peyser, Jessica D. Faul, Christian Fuchsberger, David Cesarini, Alex S. F. Doney, Janine F. Felix, Cornelius A. Rietveld, Jagadish Vangipurapu, Tanguy Corre, Line Skotte, Rajkumar Dorajoo, Catherine Igartua, Meena Kumari, Nona Sotoodehnia, Leonard H. van den Berg, Najaf Amin, Dale R. Nyholt, Harry Campbell, Massimiliano Cocca, Scott D. Gordon, Patrik K. E. Magnusson, John C. Chambers, Traci M. Bartz, Mike A. Nalls, Tin Aung, Nduna Dzimiri, Colin N. A. Palmer, Rob M. van Dam, Johanna Kuusisto, Russell P. Tracy, Anna Damulina, Pierre-Emmanuel Morange, Sylvain Foisy, Jing Hua Zhao, Nicholas G. Martin, Ching-Yu Cheng, Mariaelisa Graff, Rashmi B. Prasad, Alice Stanton, David-Alexandre Trégouët, Yu Guo, Helen R. Warren, Lyn R. Griffiths, Weihua Meng, Annika Tillander, Christa Meisinger, Albert V. Smith, Mark I. McCarthy, Jingyun Yang, Marine Germain, Neil Small, Linda Broer, Vilmundur Gudnason, Gunnar K. Pálsson, Michele K. Evans, Alexander Teumer, Mark J. Caulfield, Giorgia Girotto, Thomas Lumley, Tinca J. C. Polderman, Wei Zhao, Carlos A. Aguilar-Salinas, Jari Lahti, Matthew L. Albert, Yechiel Friedlander, Veikko Salomaa, Iona Y Millwood, Jan H. Veldink, Archie Campbell, Andres Metspalu, Ulf Gyllensten, Grant W. Montgomery, Veronique Vitart, Jai Rup Singh, Saima Afaq, Alan R. Shuldiner, Miao-Li Chee, Adebowale Adeyemo, Jennifer A. Smith, David A. van Heel, Jaspal S. Kooner, Daniela Toniolo, Cristian Pattaro, Jerome I. Rotter, John Whitfield, Melissa C. Smart, Kari E. North, Salman M. Tajuddin, Tallapragada Divya Sri Priyanka, Christopher A. Haiman, Diane M. Becker, Bernhard K. Krämer, Paul Elliott, Lihua Wang, He Gao, Patrick Sulem, Jinyan Huang, Chiea Chuen Khor, Ruifang Li-Gao, Åsa Johansson, Winfried März, Shai Carmi, Ilaria Gandin, Eric Boerwinkle, Gardar Sveinbjornsson, Saskia P. Hagenaars, Sander W. van der Laan, Gerard Pasterkamp, E-Shyong Tai, Hagit Hochner, Yih Chung Tham, Kent D. Taylor, Kari Stefansson, Matt J. Neville, Craig E. Pennell, Yanchun Bao, Annelot M. Dekker, Helena Schmidt, Mehdi Hedayati, Joshua Elliott, Ian J. Deary, Iris E. Jansen, Judith B. Borja, Edith Hofer, Martin Gögele, Igor Rudan, Lude Franke, Matthias Munz, Folkert W. Asselbergs, Bengt Sennblad, Imo Hofer, John D. Rioux, Pim van der Harst, Bahareh Sedaghati-khayat, Giovanni Cugliari, Morris A. Swertz, Francine Grodstein, Erwin P. Bottinger, Carol A. Wang, Andre Franke, Brian F. Meyer, Adele M. Taylor, Klodian Dhana, Jian'an Luan, Constance Turman, Robert A. Scott, May E. Montasser, Alison Pattie, Marco Brumat, Liming Li, Heiner Boeing, Karen L. Mohlke, Clemens Baumbach, Bishwa Raj Sapkota, Unnur Thorsteinsdottir, Naveed Sattar, Amy R. Bentley, Matthias B. Schulze, Ivana Kolcic, Stella Trompet, Sarah E. Harris, Ayo P. Doumatey, Charumathi Sabanayagam, David Eccles, Mary F. Feitosa, Jost B. Jonas, Massimo Mezzavilla, Mark O. Goodarzi, David Ellinghaus, Heribert Schunkert, Christian Gieger, Heikki V. Huikuri, Lingyao Zeng, Johan G. Eriksson, Woon-Puay Koh, Yucheng Jia, Gurpreet Singh Wander, James F. Wilson, Torgny Karlsson, Steven C. Hunt, Weihua Zhang, Maria Pina Concas, Zoltán Kutalik, Rebecca Rohde, Chittaranjan S. Yajnik, Yasaman Saba, Dabeeru C. Rao, Robin G. Walters, Reedik Mägi, Marie Loh, Eero Vuoksimaa, Josyf C. Mychaleckyj, Katri Räikkönen, Philippe Goyette, M. Arfan Ikram, Alicia Huerta-Chagoya, David J. Porteous, Teresa Nutile, J. Wouter Jukema, Noha A. Yousri, Yoichiro Kamatani, Maryam S. Daneshpour, Babette S. Zemel, Rona J. Strawbridge, Tien Yin Wong, Claudia Langenberg, Amy Moore, Marcus E. Kleber, Fereidoun Azizi, Avner Halevy, Erika Salvi, Francis S. Collins, Markku Laakso, Tim Kacprowski, S. Sunna Ebenesersdóttir, William R. Scott, Michael Boehnke, Jin-Fang Chai, Markus Perola, Nicola Pirastu, Wayne Huey-Herng Sheu, Robert Karlsson, Lenore J. Launer, Lili Milani, Renée de Mutsert, Fernando Rivadeneira, David A. Bennett, Nicola D. Kerrison, Paolo Manunta, Graciela E. Delgado, Magnus Johannesson, Carolina Medina-Gomez, Alanna C. Morrison, Kay-Tee Khaw, Jian-Min Yuan, Jaakko Kaprio, Melanie Waldenberger, Ralf Ewert, Hugoline G. de Haan, Andrew A. Hicks, Yukinori Okada, Maria Sabater-Lleal, Marilyn C. Cornelis, Stephanie J. London, Federica Rizzi, Jeanette Erdmann, Marina Ciullo, Michiaki Kubo, University of Edinburgh, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Osaka University Graduate School of Medicine, Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE genetics [Reykjavik], Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR), Area Science Park, Università degli studi di Trieste = University of Trieste, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Harbor UCLA Medical Center [Torrance, Ca.], Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Pop. Genetics, CNR, Sassari, Shardna life science Pula Cagliari, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Medstar Research Institute, Florida State University [Tallahassee] (FSU), University Medical Center [Utrecht], Centre for Population Health Sciences, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), California State University [Sacramento], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Medical University Graz, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Frederick National Laboratory for Cancer Research (FNLCR), Wellcome Trust Centre of Human Genetics, University of Oxford, Department of Epidemiology, German Institute of Human Nutrition, University Medical Center Groningen [Groningen] (UMCG), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Department of Medicine, Surgery, and Dentistry, University of Milano, Icelandic Heart Association, Kopavogur, Iceland., Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Glasgow, Department of Cardiology, Leiden University Medical Center, Leiden, Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, Queen Mary University of London (QMUL), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Genentech, Inc., Genentech, Inc. [San Francisco], University of Tartu, Duke-NUS Medical School [Singapore], Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Human Genome Sequencing Center, Baylor College of Medicine, Baylor College of Medicine (BCM), Baylor University-Baylor University, University of San Carlos, Office of Population Studies Foundation, Icahn School of Medicine at Mount Sinai [New York] (MSSM), King‘s College London, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), University of Oxford, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Department of Internal Medicine B, University Medicine Greifswald, Greifswald, University of Chicago, University of Huddersfield, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Section on Nephrology [Winston-Salem, NC, USA] (Department of Internal Medicine), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center-Wake Forest Baptist Medical Center, Radcliffe Department of Medicine [Oxford], Harvard School of Public Health, Kunming University of Science and Technology (KMUST), Sans affiliation, University of Southern California (USC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), National University of Singapore (NUS), Experimental Cardiology Laboratory (ECL), Unirversity Medical Center, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Department of Medical Genetics, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Capital Normal University [Beijing], Saw Swee Hock School of Public Health, National Institute for Environmental Health Sciences Research Triangle Park, Brown University, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, Toyota Research Institute, Helmholtz Zentrum München = German Research Center for Environmental Health, Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Timone [CHU - APHM] (TIMONE), Metacohorts Consortium, Universiteit Leiden, Institute of Clinical Chemistry and Laboratory Medicine, University of Groningen [Groningen], Medical Research Concil Epidemiology Unit, Institute of Medical Science, Faculty of Medicine, Genetics and Pathology, Imperial College London, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Brigham and Women's Hospital [Boston], Erasmus University Rotterdam, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Stockholm Bioinformatics Center (SBC), Stockholm University, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, INRH, Department of Genetics, Los Angeles Biomedical Research Institute (LA BioMed), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Western General Hospital, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Medical Research Council, Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute-University of Pittsburgh Graduate School of Public Health, Zhengzhou University of Light Industry, Department of Electrical and Electronic Engineering [Niigata Univ.], Niigata University, Genetic Epidemiology Unit, University College of London [London] (UCL), Aston Business School, Aston University [Birmingham], Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], Centre Hospitalier Universitaire Vaudois (CHUV), Pennington Biomedical Research Center, University of Washington [Seattle], Guy's and St Thomas' Hospitals, Northwestern Polytechnical University [Xi'an] (NPU), Department of Social Medicine, University of Bristol [Bristol], Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, Department of Internal Medicine, Institute of Clinical Molecular Biology, Kiel University, Medizinische Klinik II, Universität zu Lübeck = University of Lübeck [Lübeck], Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina, Institute for Social Research, University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Lund University [Lund], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Medical Research Center Oulu, University of Oulu, University of Utah School of Medicine [Salt Lake City], The Generation R Study, Pediatrics, Epidemiology, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], Universität Heidelberg [Heidelberg] = Heidelberg University, Interuniversity Cardiology Institute Netherlands, School of Public Health, University of Michigan [Dearborn], Department of Epidemiology and Public Health, University of Kuopio, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Epidemiology and Biobank PopGen, Department of Biostatistics, University of Washington, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), QIMR Berghofer Medical Research Institute, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, University of Illinois [Chicago] (UIC), University of Illinois System, Experimental Cardiology Laboratory, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Functional Genomics, Erasmus Medical Centre, National Human Genome Research Institute (NHGRI), School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Pathological Biochemistry, Royal Infirmary, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Institute of Metabolic Science, MRC, University of Maryland School of Medicine [Baltimore, MD, USA], Centre for Molecular Epidemiology, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, IRCCS San Raffaele Scientific Institute [Milan, Italie], U937, Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Michigan System, HMNC Brain Health, Singapore Eye Research Institute, Partenaires INRAE, Institut d'Électronique et des Technologies du numéRique (IETR), Université de Nantes (UN)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Groningen, Department of Genomics of Common Disease, Department of Microbiology, The Freeman Hospital, Department Biostatistics University of North Carolina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Clark, D. W., Okada, Y., Moore, K. H. S., Mason, D., Pirastu, N., Gandin, I., Mattsson, H., Barnes, C. L. K., Lin, K., Zhao, J. H., Deelen, P., Rohde, R., Schurmann, C., Guo, X., Giulianini, F., Zhang, W., Medina-Gomez, C., Karlsson, R., Bao, Y., Bartz, T. M., Baumbach, C., Biino, G., Bixley, M. J., Brumat, M., Chai, J. -F., Corre, T., Cousminer, D. L., Dekker, A. M., Eccles, D. A., van Eijk, K. R., Fuchsberger, C., Gao, H., Germain, M., Gordon, S. D., de Haan, H. G., Harris, S. E., Hofer, E., Huerta-Chagoya, A., Igartua, C., Jansen, I. E., Jia, Y., Kacprowski, T., Karlsson, T., Kleber, M. E., Li, S. A., Li-Gao, R., Mahajan, A., Matsuda, K., Meidtner, K., Meng, W., Montasser, M. E., van der Most, P. J., Munz, M., Nutile, T., Palviainen, T., Prasad, G., Prasad, R. B., Priyanka, T. D. S., Rizzi, F., Salvi, E., Sapkota, B. R., Shriner, D., Skotte, L., Smart, M. C., Smith, A. V., van der Spek, A., Spracklen, C. N., Strawbridge, R. J., Tajuddin, S. M., Trompet, S., Turman, C., Verweij, N., Viberti, C., Wang, L., Warren, H. R., Wootton, R. E., Yanek, L. R., Yao, J., Yousri, N. A., Zhao, W., Adeyemo, A. A., Afaq, S., Aguilar-Salinas, C. A., Akiyama, M., Albert, M. L., Allison, M. A., Alver, M., Aung, T., Azizi, F., Bentley, A. R., Boeing, H., Boerwinkle, E., Borja, J. B., de Borst, G. J., Bottinger, E. P., Broer, L., Campbell, H., Chanock, S., Chee, M. -L., Chen, G., Chen, Y. -D. I., Chen, Z., Chiu, Y. -F., Cocca, M., Collins, F. S., Concas, M. P., Corley, J., Cugliari, G., van Dam, R. M., Damulina, A., Daneshpour, M. S., Day, F. R., Delgado, G. E., Dhana, K., Doney, A. S. F., Dorr, M., Doumatey, A. P., Dzimiri, N., Ebenesersdottir, S. S., Elliott, J., Elliott, P., Ewert, R., Felix, J. F., Fischer, K., Freedman, B. I., Girotto, G., Goel, A., Gogele, M., Goodarzi, M. O., Graff, M., Granot-Hershkovitz, E., Grodstein, F., Guarrera, S., Gudbjartsson, D. F., Guity, K., Gunnarsson, B., Guo, Y., Hagenaars, S. P., Haiman, C. A., Halevy, A., Harris, T. B., Hedayati, M., van Heel, D. A., Hirata, M., Hofer, I., Hsiung, C. A., Huang, J., Hung, Y. -J., Ikram, M. A., Jagadeesan, A., Jousilahti, P., Kamatani, Y., Kanai, M., Kerrison, N. D., Kessler, T., Khaw, K. -T., Khor, C. C., de Kleijn, D. P. V., Koh, W. -P., Kolcic, I., Kraft, P., Kramer, B. K., Kutalik, Z., Kuusisto, J., Langenberg, C., Launer, L. J., Lawlor, D. A., Lee, I. -T., Lee, W. -J., Lerch, M. M., Li, L., Liu, J., Loh, M., London, S. J., Loomis, S., Lu, Y., Luan, J., Magi, R., Manichaikul, A. W., Manunta, P., Masson, G., Matoba, N., Mei, X. W., Meisinger, C., Meitinger, T., Mezzavilla, M., Milani, L., Millwood, I. Y., Momozawa, Y., Moore, A., Morange, P. -E., Moreno-Macias, H., Mori, T. A., Morrison, A. C., Muka, T., Murakami, Y., Murray, A. D., de Mutsert, R., Mychaleckyj, J. C., Nalls, M. A., Nauck, M., Neville, M. J., Nolte, I. M., Ong, K. K., Orozco, L., Padmanabhan, S., Palsson, G., Pankow, J. S., Pattaro, C., Pattie, A., Polasek, O., Poulter, N., Pramstaller, P. P., Quintana-Murci, L., Raikkonen, K., Ralhan, S., Rao, D. C., van Rheenen, W., Rich, S. S., Ridker, P. M., Rietveld, C. A., Robino, A., van Rooij, F. J. A., Ruggiero, D., Saba, Y., Sabanayagam, C., Sabater-Lleal, M., Sala, C. F., Salomaa, V., Sandow, K., Schmidt, H., Scott, L. J., Scott, W. R., Sedaghati-Khayat, B., Sennblad, B., van Setten, J., Sever, P. J., Sheu, W. H. -H., Shi, Y., Shrestha, S., Shukla, S. R., Sigurdsson, J. K., Sikka, T. T., Singh, J. R., Smith, B. H., Stancakova, A., Stanton, A., Starr, J. M., Stefansdottir, L., Straker, L., Sulem, P., Sveinbjornsson, G., Swertz, M. A., Taylor, A. M., Taylor, K. D., Terzikhan, N., Tham, Y. -C., Thorleifsson, G., Thorsteinsdottir, U., Tillander, A., Tracy, R. P., Tusie-Luna, T., Tzoulaki, I., Vaccargiu, S., Vangipurapu, J., Veldink, J. H., Vitart, V., Volker, U., Vuoksimaa, E., Wakil, S. M., Waldenberger, M., Wander, G. S., Wang, Y. X., Wareham, N. J., Wild, S., Yajnik, C. S., Yuan, J. -M., Zeng, L., Zhang, L., Zhou, J., Amin, N., Asselbergs, F. W., Bakker, S. J. L., Becker, D. M., Lehne, B., Bennett, D. A., van den Berg, L. H., Berndt, S. I., Bharadwaj, D., Bielak, L. F., Bochud, M., Boehnke, M., Bouchard, C., Bradfield, J. P., Brody, J. A., Campbell, A., Carmi, S., Caulfield, M. J., Cesarini, D., Chambers, J. C., Chandak, G. R., Cheng, C. -Y., Ciullo, M., Cornelis, M., Cusi, D., Smith, G. D., Deary, I. J., Dorajoo, R., van Duijn, C. M., Ellinghaus, D., Erdmann, J., Eriksson, J. G., Evangelou, E., Evans, M. K., Faul, J. D., Feenstra, B., Feitosa, M., Foisy, S., Franke, A., Friedlander, Y., Gasparini, P., Gieger, C., Gonzalez, C., Goyette, P., Grant, S. F. A., Griffiths, L. R., Groop, L., Gudnason, V., Gyllensten, U., Hakonarson, H., Hamsten, A., van der Harst, P., Heng, C. -K., Hicks, A. A., Hochner, H., Huikuri, H., Hunt, S. C., Jaddoe, V. W. V., De Jager, P. L., Johannesson, M., Johansson, A., Jonas, J. B., Jukema, J. W., Junttila, J., Kaprio, J., Kardia, S. L. R., Karpe, F., Kumari, M., Laakso, M., van der Laan, S. W., Lahti, J., Laudes, M., Lea, R. A., Lieb, W., Lumley, T., Martin, N. G., Marz, W., Matullo, G., Mccarthy, M. I., Medland, S. E., Merriman, T. R., Metspalu, A., Meyer, B. F., Mohlke, K. L., Montgomery, G. W., Mook-Kanamori, D., Munroe, P. B., North, K. E., Nyholt, D. R., O'Connell, J. R., Ober, C., Oldehinkel, A. J., Palmas, W., Palmer, C., Pasterkamp, G. G., Patin, E., Pennell, C. E., Perusse, L., Peyser, P. A., Pirastu, M., Polderman, T. J. C., Porteous, D. J., Posthuma, D., Psaty, B. M., Rioux, J. D., Rivadeneira, F., Rotimi, C., Rotter, J. I., Rudan, I., Den Ruijter, H. M., Sanghera, D. K., Sattar, N., Schmidt, R., Schulze, M. B., Schunkert, H., Scott, R. A., Shuldiner, A. R., Sim, X., Small, N., Smith, J. A., Sotoodehnia, N., Tai, E. -S., Teumer, A., Timpson, N. J., Toniolo, D., Tregouet, D. -A., Tuomi, T., Vollenweider, P., Wang, C. A., Weir, D. R., Whitfield, J. B., Wijmenga, C., Wong, T. -Y., Wright, J., Yang, J., Yu, L., Zemel, B. S., Zonderman, A. B., Perola, M., Magnusson, P. K. E., Uitterlinden, A. G., Kooner, J. S., Chasman, D. I., Loos, R. J. F., Franceschini, N., Franke, L., Haley, C. S., Hayward, C., Walters, R. G., Perry, J. R. B., Esko, T., Helgason, A., Stefansson, K., Joshi, P. K., Kubo, M., Wilson, J. F., Læknadeild (HÍ), Faculty of Medicine (UI), Félagsfræði-, mannfræði- og þjóðfræðideild (HÍ), Faculty of Sociology, Anthropology and Folkloristics (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Félagsvísindasvið (HÍ), School of Social Sciences (UI), Háskóli Íslands, University of Iceland, Clark, David W [0000-0002-1025-9185], Okada, Yukinori [0000-0002-0311-8472], Moore, Kristjan H S [0000-0002-9579-4362], Mason, Dan [0000-0002-0026-9216], Pirastu, Nicola [0000-0002-5363-3886], Gandin, Ilaria [0000-0003-3196-2491], Deelen, Patrick [0000-0002-5654-3966], Schurmann, Claudia [0000-0003-4158-9192], Medina-Gomez, Carolina [0000-0001-7999-5538], Karlsson, Robert [0000-0002-8949-2587], Bao, Yanchun [0000-0002-6102-5098], Biino, Ginevra [0000-0002-9936-946X], Brumat, Marco [0000-0003-3268-039X], Chai, Jin-Fang [0000-0003-3770-1137], Eccles, David A [0000-0003-4634-4995], Gordon, Scott 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C. [0000-0001-5564-301X], Porteous, David J [0000-0003-1249-6106], Rioux, John D [0000-0001-7560-8326], Rivadeneira, Fernando [0000-0001-9435-9441], Rotimi, Charles [0000-0001-5759-053X], Rotter, Jerome I [0000-0001-7191-1723], Rudan, Igor [0000-0001-6993-6884], Sattar, Naveed [0000-0002-1604-2593], Sim, Xueling [0000-0002-1233-7642], Smith, Jennifer A [0000-0002-3575-5468], Teumer, Alexander [0000-0002-8309-094X], Timpson, Nicholas J [0000-0002-7141-9189], Tuomi, Tiinamaija [0000-0002-8306-6202], Wang, Carol A [0000-0002-4301-3974], Weir, David R [0000-0002-1661-2402], Whitfield, John B [0000-0002-1103-0876], Magnusson, Patrik K. E. [0000-0002-7315-7899], Uitterlinden, André G [0000-0002-7276-3387], Loos, Ruth J. F. [0000-0002-8532-5087], Franke, Lude [0000-0002-5159-8802], Haley, Chris S [0000-0002-9811-0210], Hayward, Caroline [0000-0002-9405-9550], Walters, Robin G [0000-0002-9179-0321], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Apollo - University of Cambridge Repository, Moore, Kristjan HS [0000-0002-9579-4362], Luan, Jian'an [0000-0003-3137-6337], Grant, Struan FA [0000-0003-2025-5302], Jaddoe, Vincent WV [0000-0003-2939-0041], Polderman, Tinca JC [0000-0001-5564-301X], Magnusson, Patrik KE [0000-0002-7315-7899], Loos, Ruth JF [0000-0002-8532-5087], Neurology, Human genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Institute for Molecular Medicine Finland, Department of Psychology and Logopedics, University Management, Developmental Psychology Research Group, Staff Services, Cognitive and Brain Aging, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Genetic Epidemiology, Helsinki Collegium for Advanced Studies, HUS Abdominal Center, Endokrinologian yksikkö, Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), University of Trieste, Université de Lausanne (UNIL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Consiglio Nazionale delle Ricerche (CNR), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris], University of Oxford [Oxford], Medical Genetics, Dept. RSD and Public Health, IRCCS-Burlo Garofolo/University of Trieste, sans affiliation, Helmholtz-Zentrum München (HZM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Cardiovascular Science, University College London, Hammersmith Hospital NHS Imperial College Healthcare-Imperial College London, Universität zu Lübeck [Lübeck], University of Ioannina Medical School, Università degli studi di Napoli Federico II-RISSC-Lab, Universität Heidelberg [Heidelberg], University of Turin, University of California-University of California, Nantes Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Université de Nantes (UN)-Université de Rennes 1 (UR1), Erasmus MC other, Internal Medicine, and Applied Economics

Subjects
0301 basic medicine, 631/208/1397, Chemistry(all), Health Status, [SDV]Life Sciences [q-bio], LOCI, General Physics and Astronomy, MESH: Haplotype, MESH: Cognition, 030105 genetics & heredity, Runs of Homozygosity, Biochemistry, Consanguinity, Cognition, Inbreeding depression, 2.1 Biological and endogenous factors, Body Size, Inbreeding, Skyldleikarækt, Aetiology, Human phenotypes, lcsh:Science, MESH: Health Status, Genetics, Multidisciplinary, Inbreeding Depression, Confounding, Homozygote, RUNS, 631/208/205, 631/208/721, 3. Good health, genomic inbreeding coefficients, MESH: Risk-Taking, 631/208/730, Autozygosit, homozygosity, Erfðarannsóknir, Medical Genetics, genomic inbreeding coefficient, MESH: Homozygote, Offspring, Science, Autozygosity, Blóðsifjar, 610 Medicine & health, Biology, INBREEDING DEPRESSION, HOMOZYGOSITY, FERTILITY, QUANTIFICATION, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, Association, 03 medical and health sciences, Risk-Taking, 360 Social problems & social services, Journal Article, Humans, ddc:610, Allele, Alleles, Medicinsk genetik, Genetic association study, MESH: Consanguinity, MESH: Body Size, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), MESH: Alleles, Haplotype, MESH: Fertility, General Chemistry, Brain Disorders, MESH: Inbreeding Depression, 030104 developmental biology, Fertility, Haplotypes, Genetic markers, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Genetics and Molecular Biology(all)
Abstract

Publisher's version (útgefin grein)., In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.

Published
2019

46. Effects of Intensive Glycemic Control on Clinical Outcomes Among Patients With Type 2 Diabetes With Different Levels of Cardiovascular Risk and Hemoglobin A

Author

Jingyan, Tian, Toshiaki, Ohkuma, Mark, Cooper, Stephen, Harrap, Giuseppe, Mancia, Neil, Poulter, Ji-Guang, Wang, Sophia, Zoungas, Mark, Woodward, and John, Chalmers

Subjects
Blood Glucose, Glycated Hemoglobin, Male, Glycemic Control, Middle Aged, Prognosis, Drug Combinations, Treatment Outcome, Diabetes Mellitus, Type 2, Double-Blind Method, Cardiovascular Diseases, Heart Disease Risk Factors, Risk Factors, Delayed-Action Preparations, Gliclazide, Indapamide, Perindopril, Humans, Hypoglycemic Agents, Female, Aged
Abstract

To study whether the effects of intensive glycemic control on major vascular outcomes (a composite of major macrovascular and major microvascular events), all-cause mortality, and severe hypoglycemia events differ among participants with different levels of 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and hemoglobin AWe studied the effects of more intensive glycemic control in 11,071 patients with type 2 diabetes (T2D), without missing values, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, using Cox models.During 5 years' follow-up, intensive glycemic control reduced major vascular events (hazard ratio [HR] 0.90 [95% CI 0.83-0.98]), with the major driver being a reduction in the development of macroalbuminuria. There was no evidence of differences in the effect, regardless of baseline ASCVD risk or HbAThe major benefits for patients with T2D in ADVANCE did not substantially differ across levels of baseline ASCVD risk and HbA

Published
2019

47. [Lancet Commission on Hypertension Group position statement on the global improvement of accuracy standards for devices that measure blood pressurePosicionamento do Grupo da

Author

James E, Sharman, Eoin, O'Brien, Bruce, Alpert, Aletta E, Schutte, Christian, Delles, Michael Hecht, Olsen, Roland, Asmar, Neil, Atkins, Eduardo, Barbosa, David, Calhoun, Norm R C, Campbell, John, Chalmers, Ivor, Benjamin, Garry, Jennings, Stéphane, Laurent, Pierre, Boutouyrie, Patricio, Lopez-Jaramillo, Richard J, McManus, Anastasia S, Mihailidou, Pedro, Ordunez, Raj, Padwal, Paolo, Palatini, Gianfranco, Parati, Neil, Poulter, Michael K, Rakotz, Clive, Rosendorff, Francesca, Saladini, Angelo, Scuteri, Weimar Sebba, Barroso, Myeong-Chan, Cho, Ki-Chul, Sung, Raymond R, Townsend, Ji-Guang, Wang, Tine Willum, Hansen, Gregory, Wozniak, and George, Stergiou

Subjects
Informe Especial, equipos diagnósticos, Biomedical technology, international health, equipamentos para diagnóstico, Salud internacional, tecnología biomédica, Tecnologia biomédica, diagnostic equipment, estándares de referencia, padrões de referência, saúde global, reference standard
Abstract

The Lancet Commission on Hypertension identified that a key action to address the worldwide burden of high blood pressure (BP) was to improve the quality of BP measurements by using BP devices that have been validated for accuracy. Currently, there are over 3 000 commercially available BP devices, but many do not have published data on accuracy testing according to established scientific standards. This problem is enabled through weak or absent regulations that allow clearance of devices for commercial use without formal validation. In addition, new BP technologies have emerged (e.g. cuffless sensors) for which there is no scientific consensus regarding BP measurement accuracy standards. Altogether, these issues contribute to the widespread availability of clinic and home BP devices with limited or uncertain accuracy, leading to inappropriate hypertension diagnosis, management and drug treatment on a global scale. The most significant problems relating to the accuracy of BP devices can be resolved by the regulatory requirement for mandatory independent validation of BP devices according to the universally-accepted International Organization for Standardization Standard. This is a primary recommendation for which there is an urgent international need. Other key recommendations are development of validation standards specifically for new BP technologies and online lists of accurate devices that are accessible to consumers and health professionals. Recommendations are aligned with WHO policies on medical devices and universal healthcare. Adherence to recommendations would increase the global availability of accurate BP devices and result in better diagnosis and treatment of hypertension, thus decreasing the worldwide burden from high BP.A Comissão Lancet sobre Hipertensão Arterial identificou que uma iniciativa central para enfrentar a carga mundial da hipertensão arterial seria a melhoria na qualidade da mensuração da pressão arterial pelo uso aparelhos de pressão arterial validados quanto à acurácia. Atualmente, existem mais de 3 000 aparelhos de pressão arterial disponíveis comercialmente; entretanto, muitos não têm dados publicados sobre testes de acurácia realizados de acordo com padrões científicos estabelecidos. Este problema resulta de regulamentação fraca ou inexistente, o que permite a aprovação para uso comercial de dispositivos sem validação formal. Além disso, surgiram novas tecnologias de mensuração da pressão arterial (por exemplo, sensores sem algemas) sem consenso científico quanto aos padrões de acurácia. No conjunto, essas questões contribuem para a oferta generalizada de dispositivos de pressão arterial clínica e domiciliar com acurácia limitada ou incerta, levando a diagnóstico, gerenciamento e tratamento inadequados da hipertensão em escala global. Os problemas mais significativos relacionados com a acurácia dos dispositivos de pressão arterial podem ser resolvidos por regulamentação que imponha a obrigatoriedade de validação independente dos aparelhos de pressão arterial, de acordo com a norma universalmente aceita pela Organização Internacional de Normalização. Esta é uma recomendação fundamental para a qual existe uma necessidade internacional urgente. Outras recomendações essenciais incluem o desenvolvimento de padrões de validação especificamente para novas tecnologias de mensuração da pressão arterial e listas

Published
2019

48. Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

Author

Michael Boehnke, Anke R. Hammerschlag, Stavroula Kanoni, Nilesh J. Samani, Stefan Blankenberg, Arpana Agrawal, Ersin Yavas, Chris Hsu, Dominique Arveiler, Giovanni Veronesi, Sarah E. Harris, Guillaume Lettre, Leah Wetherill, Helen R. Warren, M Samuel, Manav Kapoor, Praveen Surendran, Mengzhen Liu, Massimo Mangino, Abdulla Al Shafi Majumder, Chiara Batini, Jeff Haessler, Anton J. M. De Craen, Matt McGue, Laura J. Bierut, Yi Ling Chou, Markku Laakso, Ian J. Deary, Rebecca Rohde, Nhung Le, David Schlessinger, J. Dylan Weissenkampen, Claudia Langenberg, Tim D. Spector, Paul W. Franks, John P. Rice, Philippe M. Frossard, Hanieh Yaghootkar, Janie Corley, Frank Kee, J. Wouter Jukema, Pim van der Harst, Dermot F. Reily, Jenny Chang-Claude, Nicholas G. Martin, Tatiana Foroud, Sune F. Nielsen, Charles Kooperberg, Rudolf A. de Boer, Francesco Cucca, Paul D.P. Pharoah, Alex P. Reiner, Daniel R. Barnes, Anders Mälarstig, Jonathan Marten, Henry Völzke, Yu Jiang, Jukka Kontto, J Danesh, Antonis C. Antoniou, Andrew C. Heath, Nicholas J. Wareham, Joanna M. M. Howson, Alison Goate, Olov Rolandsson, Frida Renström, Chu Chen, Vinicius Tragante, Matt J. Neville, Kathleen Stirrups, Clemens Baumbach, Colin N. A. Palmer, Adam S. Butterworth, William G. Iacono, Naveed Sattar, Ian P. Hall, Daniel O. Stram, Giorgio Pistis, Jan-Håkan Jansson, Jaakko Kaprio, David R. Weir, David P. Strachan, Martin D. Tobin, Folkert W. Asselbergs, John M. Starr, Stefan Weiss, Thomas F. Vogt, Riccardo E. Marioni, Maarten Hoek, Jessica Tyrrell, Hilary A. Tindle, Alison M. Dunning, Anu Loukola, Joe Dennis, Victoria E. Jackson, Louise V. Wain, Eleftheria Zeggini, Weihua Zhang, Yaming Shao, Kari Kuulasmaa, Elisabeth Altmaier, Jean-Claude Tardif, Jian Gong, A. Mesut Erzurumluoglu, Andries R. van der Leij, Kari E. North, Anna F. Dominiczak, Martina Müller-Nurasyid, Scott I. Vrieze, Sarah Bertelsen, Markus Perola, Evangelos Evangelou, Chris J. Packard, Gonçalo R. Abecasis, Robert A. Scott, S. Trompet, Jennifer A. Smith, H. Steven Scholte, Timothy M. Frayling, Danielle Posthuma, Ian Ford, Douglas F. Easton, Børge Grønne Nordestgaard, Michiel L. Bots, Charles B. Eaton, Sharon L.R. Kardia, Dewan S. Alam, Xiaowei Zhan, Sean P. David, Maria Uria-Nickelsen, Dongbing Lai, Ilonca Vaartjes, Mark J. Caulfield, Valérie Turcot, Jean Ferrières, Emanuele Di Angelantonio, Robin Young, Pamela A. F. Madden, Tibor V. Varga, Asif Rasheed, Peter van der Meer, Dajiang J. Liu, Ioanna Tachmazidou, Panos Deloukas, Danish Saleheen, Evelin Mihailov, Caroline Hayward, Patricia B. Munroe, Beenish Qaiser, Jessica D. Faul, John C. Chambers, Matthias Nauck, Niek Verweij, Jordan M. Hughey, Christopher A. Haiman, Hans J. Grabe, Muriel Caslake, Saima Afaq, Jaspal S. Kooner, Tinca J. C. Polderman, Philippe Amouyel, Wei Zhao, Göran Hallmans, Andres Metspalu, Jarmo Virtamo, Carl A. Melbourne, Kaixin Zhou, Christiaan de Leeuw, Peter S. Sever, Eirini Marouli, Neil Poulter, Rajiv Chowdhury, Jian'an Luan, Deborah J. Thompson, F Karpe, Kyriaki Michailidou, David M. Brazel, Heather M. Stringham, Brein en Cognitie (Psychologie, FMG), Psychology Other Research (FMG), Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Graduate School, Experimental Vascular Medicine, ACS - Diabetes & metabolism, Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, AGEM - Digestive immunity, AGEM - Endocrinology, metabolism and nutrition, Laboratory Genetic Metabolic Diseases, Gastroenterology and Hepatology, Experimental Immunology, Radiotherapy, Cardiology, HUSLAB, Institute for Molecular Medicine Finland, Department of Public Health, Genetic Epidemiology, Barnes, Daniel [0000-0002-3781-7570], Erzurumluoglu, Mesut [0000-0003-1322-8138], Apollo - University of Cambridge Repository, Biological Psychology, and Complex Trait Genetics

Subjects
0301 basic medicine, Nonsynonymous substitution, Genome-wide association study, 3124 Neurology and psychiatry, 0302 clinical medicine, DEPENDENCE, Genotype, Databases, Genetic, SEQUENCE VARIANTS, GWAS, Exome, Non-U.S. Gov't, Oligonucleotide Array Sequence Analysis, Genetics, RISK, HERITABILITY, Research Support, Non-U.S. Gov't, Smoking, ASSOCIATION, 3. Good health, ADH1B, Phenotype, Behavioral genetics, LOW-FREQUENCY, Alcohol, Heritability, Nicotine, Tobacco, Alcohol Drinking, Non-P.H.S, Single-nucleotide polymorphism, Biology, Research Support, Polymorphism, Single Nucleotide, N.I.H, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, Genetic variation, Journal Article, Humans, Genetic Predisposition to Disease, COMMON, Biological Psychiatry, 3112 Neurosciences, Genetic Variation, Extramural, MISSENSE VARIANTS, R1, Genetic architecture, 030104 developmental biology, U.S. Gov't, 030217 neurology & neurosurgery, Research Support, U.S. Gov't, Non-P.H.S, Genome-Wide Association Study
Abstract

BackgroundSmoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk.MethodsWe analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci.ResultsMeta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals.ConclusionsRare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.

Published
2019

49. Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials

Author

Hiddo J L Heerspink, Tom Greene, Hocine Tighiouart, Ron T Gansevoort, Josef Coresh, Andrew L Simon, Tak Mao Chan, Fan Fan Hou, Julia B Lewis, Francesco Locatelli, Manuel Praga, Francesco Paolo Schena, Andrew S Levey, Lesley A Inker, Angel Sevillano, Anne-Lise Kamper, Arjan D. van Zuilen, Barry M. Brenner, Bart Maes, Benno U. Ihle, Brendan Barret, CB Leung, CC Szeto, Christina Fitzner, Christoph Wanner, Claudio Pozzi, Claudio Ponticelli Montagnino, Di Xie, Dick de Zeeuw, Edmund Lewis, Eduardo Verde, Eduardo Gutierrez, Enyu Imai, Fernando Caravaca, Fernando C. Fervenza, Fumiaki Kobayashi, Gabriella Moroni, Gavin J. Becker, Gerald J. Beck, Gerald B. Appel, Gershon Frisch, GG van Essen, Giuseppe Maschio, Giuseppe Remuzzi, Giuseppe Montogrino, Hans-Henrik Parving, Hiddo J.L. Heerspink, Hirofumi Makino, Imitiaz Jehan, Jack F.M. Wetzels, James Donadio, Jamie Dwyer, Jan van den Brand, John Kusek, John M. Lachin, Jose Luño, Julia B. Lewis, Jürgen Floege, Kaleab Z. Abebe, KM Chow, Lawrence G. Hunsicker, Lucia del Vecchio, Manno Carlo, Marian Goicoechea, Maximilian von Eynatten, Neil Poulter, Nish Chaturvedi, Patrizia Passerini, Paul E. de Jong, Peter J. Blankestijn, Philip Li, Piero Ruggenenti, Pietro Zucchelli, Priscilla S. Kincaid-Smith, Ralf-Dieter Hilgers, Raymond O. Estacio, Richard D. Rohde, Ritsuko Katafuchi, Robert D. Toto, Robert W. Schrier, Roger A. Rodby, Ronald D. Perrone, Sadayoshi Ito, Saulo Klahr, Simeone Andrulli, Svend Strandgaard, Thierry P. Hannedouche, Thomas Rauen, Ursula Verdalles, Vlado Perkovic, William Keane, Groningen Kidney Center (GKC), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and Cardiovascular Centre (CVC)

Subjects
PROTEINURIA REDUCTION, medicine.medical_specialty, NEPHROPATHY, Endocrinology, Diabetes and Metabolism, Renal function, urologic and male genital diseases, law.invention, Nephropathy, Endocrinology, Randomized controlled trial, law, Internal medicine, Clinical endpoint, Internal Medicine, Medicine, RISK, business.industry, Surrogate endpoint, urogenital system, Hazard ratio, STAGE RENAL-DISEASE, REMISSION, medicine.disease, EFFICACY, Diabetes and Metabolism, SAFETY, Albuminuria, medicine.symptom, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11], business, Kidney disease
Abstract

Background Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials.Methods In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including "chronic kidney disease", "chronic renal insufficiency", "albuminuria", "proteinuria", and "randomized controlled trial"; key inclusion criteria were quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in albuminuria and the composite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1.73 m(2), or doubling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on albuminuria to those on the clinical endpoint across studies and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the treatment effect on albuminuria.Findings We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 participants (21 206 [71%] with diabetes). Over a median follow-up of 3.4 years (IQR 2.3-4.2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0.89 (95% Bayesian credible interval [BCI] 0.13-1.70), each 30% decrease in geometric mean albuminuria by the treatment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5-45%; median R-2 0.47, 95% BCI 0.02-0.96). The association strengthened after restricting analyses to patients with baseline albuminuria of more than 30 mg/g (ie, 3.4 mg/mmol; R-2 0.72, 0.05-0.99]). For future trials, the model predicts that treatments that decrease the geometric mean albuminuria to 0.7 (ie, 30% decrease in albuminuria) relative to the control will provide an average hazard ratio (HR) for the clinical endpoint of 0.68, and 95% of sufficiently large studies would have HRs between 0.47 and 0.95.Interpretation Our results support a role for change in albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain. Copyright (c) 2019 Elsevier Ltd. All rights reserved.

Published
2019

50. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals

Author

Dennis O. Mook-Kanamori, J M Gaziano, Harst Pvd., Derek Klarin, K A Birdwell, Josh C. Denny, Martin Farrall, Thibaud Boutin, Najim Lahrouchi, Nabi Shah, Scott M. Damrauer, Cecilia P. Chung, Neil Poulter, Herzig K-H., E E Siew, John Concato, Yan V. Sun, Sara M. Willems, Louise V. Wain, Philip S. Tsao, Massimo Mangino, Wei W-Q., Ioanna Ntalla, Brian S. Mautz, David Schlessinger, Daniel I. Chasman, Branwen J. Hennig, Christopher Newton-Cheh, Michael E. Matheny, Palmer Cna., Caroline Hayward, Zhao J-H., Eleftheria Zeggini, Paul Elliott, C M Lindgren, Praveen Surendran, Csaba P. Kovesdy, Jacob M. Keaton, Chengxiang Qiu, Claudia Langenberg, Christopher Oldmeadow, Stéphanie Debette, D.R. Velez Edwards, Evangelos Evangelou, Howson Jmm., Adriana M. Hung, Yaomin Xu, Nicholas J. Wareham, James P. Cook, Scott L. DuVall, Peter Almgren, Jacklyn N. Hellwege, Sébastien Thériault, Helen R. Warren, Jian'an Luan, Ching-Ti Liu, Christopher J. O'Donnell, Michael Boehnke, Peter S. Sever, Ruifang Li-Gao, Cassianne Robinson-Cohen, Robert A. Scott, Muralidharan Sargurupremraj, Mark J. Caulfield, Jarvelin M-R., Tim D. Spector, Todd L. Edwards, Elena V. Feofanova, Francesco Cucca, Jihwan Park, Savita Karthikeyan, J C Smith, Wilson Pwf., Markku Laakso, Ayush Giri, Christianne L. Roumie, Rojesh Shrestha, Claudia P. Cabrera, Kelly Cho, Laura J. Scott, Elvis A. Akwo, Yu Wang, Tom G. Richardson, Patricia B. Munroe, Eric S. Torstenson, Katalin Susztak, John Attia, Bruce M. Psaty, Aldi T. Kraja, Olle Melander, Nicholas J. Timpson, George Dedoussis, Paul M. Ridker, Niek Verweij, David Conen, Philippe Amouyel, Otis D. Wilson, Nuno Sepúlveda, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiology, ACS - Heart failure & arrhythmias, Cardiovascular Centre (CVC), Luan, Jian'an [0000-0003-3137-6337], Zhao, Jing Hua [0000-0003-4930-3582], Surendran, Praveen [0000-0002-4911-6077], Karthikeyan, Savita [0000-0002-4798-5746], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Howson, Joanna [0000-0001-7618-0050], and Apollo - University of Cambridge Repository

Subjects
Male, LOCI, Gene Expression, Physiology, Blood Pressure, Genome-wide association study, IDENTIFIES 8, Mice, 0302 clinical medicine, Ethnicity, PARTITIONING HERITABILITY, Genetics & Heredity, 0303 health sciences, Kidney, Blood Pressure-International Consortium of Exome Chip Studies, Million Veteran Program, PULSE PRESSURE, 11 Medical And Health Sciences, Middle Aged, Up-Regulation, 3. Good health, Pulse pressure, Kidney Tubules, medicine.anatomical_structure, VINTAGE, International Consortium for Blood Pressure, AUTOSOMAL-DOMINANT HYPERTENSION, Female, Life Sciences & Biomedicine, Understanding Society Scientific Group, Adolescent, Diastole, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Genetics, medicine, Animals, Humans, GENOME-WIDE ASSOCIATION, Gene, 030304 developmental biology, Genetic association, Science & Technology, 06 Biological Sciences, GLOBAL BURDEN, MEAN ARTERIAL, GENE, Blood pressure, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, SOLUBLE GUANYLYL CYCLASE, Transcriptome, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology
Abstract

International audience; In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

Published
2019

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