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1. Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses

Author

Liam Gaziano, Luanluan Sun, Matthew Arnold, Steven Bell, Kelly Cho, Stephen K. Kaptoge, Rebecca J. Song, Stephen Burgess, Daniel C. Posner, Katja Mosconi, Cassianne Robinson-Cohen, Amy M. Mason, Thomas R. Bolton, Ran Tao, Elias Allara, Petra Schubert, Lingyan Chen, James R. Staley, Natalie Staplin, Servet Altay, Pilar Amiano, Volker Arndt, Johan Ärnlöv, Elizabeth L.M. Barr, Cecilia Björkelund, Jolanda M.A. Boer, Hermann Brenner, Edoardo Casiglia, Paolo Chiodini, Jackie A. Cooper, Josef Coresh, Mary Cushman, Rachel Dankner, Karina W. Davidson, Renate T. de Jongh, Chiara Donfrancesco, Gunnar Engström, Heinz Freisling, Agustín Gómez de la Cámara, Vilmundur Gudnason, Graeme J. Hankey, Per-Olof Hansson, Alicia K. Heath, Ewout J. Hoorn, Hironori Imano, Simerjot K. Jassal, Rudolf Kaaks, Verena Katzke, Jussi Kauhanen, Stefan Kiechl, Wolfgang Koenig, Richard A. Kronmal, Cecilie Kyrø, Deborah A. Lawlor, Börje Ljungberg, Conor MacDonald, Giovanna Masala, Christa Meisinger, Olle Melander, Conchi Moreno Iribas, Toshiharu Ninomiya, Dorothea Nitsch, Børge G. Nordestgaard, Charlotte Onland-Moret, Luigi Palmieri, Dafina Petrova, Jose Ramón Quirós Garcia, Annika Rosengren, Carlotta Sacerdote, Masaru Sakurai, Carmen Santiuste, Matthias B. Schulze, Sabina Sieri, Johan Sundström, Valérie Tikhonoff, Anne Tjønneland, Tammy Tong, Rosario Tumino, Ioanna Tzoulaki, Yvonne T. van der Schouw, W.M. Monique Verschuren, Henry Völzke, Robert B. Wallace, S. Goya Wannamethee, Elisabete Weiderpass, Peter Willeit, Mark Woodward, Kazumasa Yamagishi, Raul Zamora-Ros, Elvis A. Akwo, Saiju Pyarajan, David R. Gagnon, Philip S. Tsao, Sumitra Muralidhar, Todd L. Edwards, Scott M. Damrauer, Jacob Joseph, Lisa Pennells, Peter W.F. Wilson, Seamus Harrison, Thomas A. Gaziano, Michael Inouye, Colin Baigent, Juan P. Casas, Claudia Langenberg, Nick Wareham, Elio Riboli, J.Michael Gaziano, John Danesh, Adriana M. Hung, Adam S. Butterworth, Angela M. Wood, Emanuele Di Angelantonio, Anna Koettgen, Jonathan Shaw, Robert Atkins, Paul Zimmet, Peter Whincup, Johann Willeit, Christoph Leitner, Anne Tybjaerg-Hansen, Peter Schnohr, Shoaib Afzal, David Lora Pablos, Cristina Martin Arriscado, Carmen Romero Ferreiro, Hannah Stocker, Ben Schöttker, Bernd Holleczek, Angela Chetrit, Lennart Welin, Kurt Svärdsudd, Lauren Lissner, Dominique Hange, Kirsten Mehlig, Dorothea Nagel, Paul E. Norman, Osvaldo Almeida, Leon Flicker, Jun Hata, Takanori Honda, Yoshihiko Furuta, Hiroyasu Iso, Akihiko Kitamura, Isao Muraki, Jukka T. Salonen, Tomi-Pekka Tuomainen, E. M. van Zutphen, N. M. van Schoor, Cinzia Lo Noce, Richard Kronmal, Georg Lappas, Peter M. Nilsson, Bo Hedblad, Jonathan Shaffer, Joseph Schwartz, Daichi Shimbo, Shinichi Sato, Mina Hayama-Terada, Simerjot Jassal, Thor Aspelund, Bolli Thorsson, Gunnar Sigurdsson, Layal Chaker, Kamran M. Ikram, Maryam Kavousi, Hugh Tunstall-Pedoe, Günay Can, Hüsniye Yüksel, Uğur Özkan, Hideaki Nakagawa, Yuko Morikawa, Masao Ishizaki, Edith Feskens, Johanna M Geleijnse, Daan Kromhout, Internal Medicine, Neurology, Epidemiology, Bell, Steven [0000-0001-6774-3149], Posner, Daniel C [0000-0002-3056-6924], Mason, Amy M [0000-0002-8019-0777], Allara, Elias [0000-0002-1634-8330], Staplin, Natalie [0000-0003-4482-4418], Arndt, Volker [0000-0001-9320-8684], Ärnlöv, Johan [0000-0002-6933-4637], Barr, Elizabeth LM [0000-0003-4284-1716], Boer, Jolanda MA [0000-0002-9714-4304], Brenner, Hermann [0000-0002-6129-1572], Casiglia, Edoardo [0000-0002-0003-3289], Chiodini, Paolo [0000-0003-0139-2264], Coresh, Josef [0000-0002-4598-0669], Cushman, Mary [0000-0002-7871-6143], Davidson, Karina W [0000-0002-9162-477X], de Jongh, Renate T [0000-0001-8414-3938], Engström, Gunnar [0000-0002-8618-9152], de la Cámara, Agustín Gómez [0000-0001-6827-6319], Gudnason, Vilmundur [0000-0001-5696-0084], Hankey, Graeme J [0000-0002-6044-7328], Hansson, Per-Olof [0000-0001-6323-0506], Heath, Alicia K [0000-0001-6517-1300], Hoorn, Ewout J [0000-0002-8738-3571], Imano, Hironori [0000-0002-6661-4254], Katzke, Verena [0000-0002-6509-6555], Kiechl, Stefan [0000-0002-9836-2514], Koenig, Wolfgang [0000-0002-2064-9603], Kronmal, Richard A [0000-0002-9897-7076], Kyrø, Cecilie [0000-0002-9083-8960], Ljungberg, Börje [0000-0002-4121-3753], MacDonald, Conor [0000-0002-4989-803X], Masala, Giovanna [0000-0002-5758-9069], Ninomiya, Toshiharu [0000-0003-1345-9032], Nordestgaard, Børge G [0000-0002-1954-7220], Onland-Moret, Charlotte [0000-0002-2360-913X], Palmieri, Luigi [0000-0002-4298-2642], Rosengren, Annika [0000-0002-5409-6605], Schulze, Matthias B [0000-0002-0830-5277], Sieri, Sabina [0000-0001-5201-172X], Sundström, Johan [0000-0003-2247-8454], Tikhonoff, Valérie [0000-0001-7846-0101], Tong, Tammy [0000-0002-0284-8959], Tzoulaki, Ioanna [0000-0002-4275-9328], van der Schouw, Yvonne T [0000-0002-4605-435X], Wannamethee, S Goya [0000-0001-9484-9977], Weiderpass, Elisabete [0000-0003-2237-0128], Willeit, Peter [0000-0002-1866-7159], Woodward, Mark [0000-0001-9800-5296], Yamagishi, Kazumasa [0000-0003-3301-5519], Zamora-Ros, Raul [0000-0002-6236-6804], Gagnon, David R [0000-0002-6367-3179], Tsao, Philip S [0000-0001-7274-9318], Edwards, Todd L [0000-0003-4318-6119], Damrauer, Scott M [0000-0001-8009-1632], Joseph, Jacob [0000-0002-7279-4896], Pennells, Lisa [0000-0002-8594-3061], Gaziano, Thomas A [0000-0002-5985-345X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nick [0000-0003-1422-2993], Hung, Adriana M [0000-0002-3203-1608], Butterworth, Adam S [0000-0002-6915-9015], Di Angelantonio, Emanuele [0000-0001-8776-6719], Apollo - University of Cambridge Repository, Gaziano, Liam, Sun, Luanluan, Arnold, Matthew, Bell, Steven, Cho, Kelly, Kaptoge, Stephen K, Song, Rebecca J, Burgess, Stephen, Posner, Daniel C, Mosconi, Katja, Robinson-Cohen, Cassianne, Mason, Amy M, Bolton, Thomas R, Tao, Ran, Allara, Elia, Schubert, Petra, Chen, Lingyan, Staley, James R, Staplin, Natalie, Altay, Servet, Amiano, Pilar, Arndt, Volker, Ärnlöv, Johan, Barr, Elizabeth L M, Björkelund, Cecilia, Boer, Jolanda M A, Brenner, Hermann, Casiglia, Edoardo, Chiodini, Paolo, Cooper, Jackie A, Coresh, Josef, Cushman, Mary, Dankner, Rachel, Davidson, Karina W, de Jongh, Renate T, Donfrancesco, Chiara, Engström, Gunnar, Freisling, Heinz, de la Cámara, Agustín Gómez, Gudnason, Vilmundur, Hankey, Graeme J, Hansson, Per-Olof, Heath, Alicia K, Hoorn, Ewout J, Imano, Hironori, Jassal, Simerjot K, Kaaks, Rudolf, Katzke, Verena, Kauhanen, Jussi, Kiechl, Stefan, Koenig, Wolfgang, Kronmal, Richard A, Kyrø, Cecilie, Lawlor, Deborah A, Ljungberg, Börje, Macdonald, Conor, Masala, Giovanna, Meisinger, Christa, Melander, Olle, Moreno Iribas, Conchi, Ninomiya, Toshiharu, Nitsch, Dorothea, Nordestgaard, Børge G, Onland-Moret, Charlotte, Palmieri, Luigi, Petrova, Dafina, Garcia, Jose Ramón Quiró, Rosengren, Annika, Sacerdote, Carlotta, Sakurai, Masaru, Santiuste, Carmen, Schulze, Matthias B, Sieri, Sabina, Sundström, Johan, Tikhonoff, Valérie, Tjønneland, Anne, Tong, Tammy, Tumino, Rosario, Tzoulaki, Ioanna, van der Schouw, Yvonne T, Monique Verschuren, W M, Völzke, Henry, Wallace, Robert B, Wannamethee, S Goya, Weiderpass, Elisabete, Willeit, Peter, Woodward, Mark, Yamagishi, Kazumasa, Zamora-Ros, Raul, Akwo, Elvis A, Pyarajan, Saiju, Gagnon, David R, Tsao, Philip S, Muralidhar, Sumitra, Edwards, Todd L, Damrauer, Scott M, Joseph, Jacob, Pennells, Lisa, Wilson, Peter W F, Harrison, Seamu, Gaziano, Thomas A, Inouye, Michael, Baigent, Colin, Casas, Juan P, Langenberg, Claudia, Wareham, Nick, Riboli, Elio, Gaziano, J Michael, Danesh, John, Hung, Adriana M, Butterworth, Adam S, Wood, Angela M, Di Angelantonio, Emanuele, Internal medicine, AMS - Ageing & Vitality, AMS - Musculoskeletal Health, Amsterdam Gastroenterology Endocrinology Metabolism, Epidemiology and Data Science, APH - Aging & Later Life, and APH - Personalized Medicine

Subjects
kidney disease, General Practice, Emerging Risk Factors Collaboration/EPIC-CVD/Million Veteran Program, Coronary Disease, coronary disease, Kidney, Malalties coronàries, 1117 Public Health and Health Services, Coronary diseases, SDG 3 - Good Health and Well-being, cardiovascular disease, Risk Factors, Physiology (medical), Diabetes Mellitus, Humans, Cardiac and Cardiovascular Systems, Prospective Studies, 1102 Cardiorespiratory Medicine and Haematology, Kardiologi, Kidney diseases, Malalties cardiovasculars, Cardiovascular Diseases, Kidney Diseases, Stroke, 1103 Clinical Sciences, Mendelian Randomization Analysis, kidney diseases, stroke, Allmänmedicin, Cardiovascular diseases, Cardiovascular System & Hematology, Malalties del ronyó, Cardiology and Cardiovascular Medicine, cardiovascular diseases
Abstract

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Published
2022

2. Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies

Author

Angela M Wood, Stephen Kaptoge, Adam S Butterworth, Peter Willeit, Samantha Warnakula, Thomas Bolton, Ellie Paige, Dirk S Paul, Michael Sweeting, Stephen Burgess, Steven Bell, William Astle, David Stevens, Albert Koulman, Randi M Selmer, W M Monique Verschuren, Shinichi Sato, Inger Njølstad, Mark Woodward, Veikko Salomaa, Børge G Nordestgaard, Bu B Yeap, Astrid Fletcher, Olle Melander, Lewis H Kuller, Beverley Balkau, Michael Marmot, Wolfgang Koenig, Edoardo Casiglia, Cyrus Cooper, Volker Arndt, Oscar H Franco, Patrik Wennberg, John Gallacher, Agustín Gómez de la Cámara, Henry Völzke, Christina C Dahm, Caroline E Dale, Manuela M Bergmann, Carlos J Crespo, Yvonne T van der Schouw, Rudolf Kaaks, Leon A Simons, Pagona Lagiou, Josje D Schoufour, Jolanda M A Boer, Timothy J Key, Beatriz Rodriguez, Conchi Moreno-Iribas, Karina W Davidson, James O Taylor, Carlotta Sacerdote, Robert B Wallace, J Ramon Quiros, Rosario Tumino, Dan G Blazer, Allan Linneberg, Makoto Daimon, Salvatore Panico, Barbara Howard, Guri Skeie, Timo Strandberg, Elisabete Weiderpass, Paul J Nietert, Bruce M Psaty, Daan Kromhout, Elena Salamanca-Fernandez, Stefan Kiechl, Harlan M Krumholz, Sara Grioni, Domenico Palli, José M Huerta, Jackie Price, Johan Sundström, Larraitz Arriola, Hisatomi Arima, Ruth C Travis, Demosthenes B Panagiotakos, Anna Karakatsani, Antonia Trichopoulou, Tilman Kühn, Diederick E Grobbee, Elizabeth Barrett-Connor, Natasja van Schoor, Heiner Boeing, Kim Overvad, Jussi Kauhanen, Nick Wareham, Claudia Langenberg, Nita Forouhi, Maria Wennberg, Jean-Pierre Després, Mary Cushman, Jackie A Cooper, Carlos J Rodriguez, Masaru Sakurai, Jonathan E Shaw, Matthew Knuiman, Trudy Voortman, Christa Meisinger, Anne Tjønneland, Hermann Brenner, Luigi Palmieri, Jean Dallongeville, Eric J Brunner, Gerd Assmann, Maurizio Trevisan, Richard F Gillum, Ian Ford, Naveed Sattar, Mariana Lazo, Simon G Thompson, Pietro Ferrari, David A Leon, George Davey Smith, Richard Peto, Rod Jackson, Emily Banks, Emanuele Di Angelantonio, John Danesh, Adam Butterworth, Monique Verschuren, Salomaa Veikko, Astrid Flecther, Manuela Bergmann, Carlos Crespo, Jolanda M.A Boer, J. Ramon Quiros, Eric B Rimm, Dan G Blazer III, Jean-Pierre Dallongeville, Richard F Gillumn, Ian Ford Ford, Simon Thompson, Epidemiology, Wood, Angela M, Kaptoge, Stephen, Butterworth, Adam S, Willeit, Peter, Warnakula, Samantha, Bolton, Thoma, Paige, Ellie, Paul, Dirk S, Sweeting, Michael, Burgess, Stephen, Bell, Steven, Astle, William, Stevens, David, Koulman, Albert, Selmer, Randi M, Verschuren, W M Monique, Sato, Shinichi, Njølstad, Inger, Woodward, Mark, Salomaa, Veikko, Nordestgaard, Børge G, Yeap, Bu B, Fletcher, Astrid, Melander, Olle, Kuller, Lewis H, Balkau, Beverley, Marmot, Michael, Koenig, Wolfgang, Casiglia, Edoardo, Cooper, Cyru, Arndt, Volker, Franco, Oscar H, Wennberg, Patrik, Gallacher, John, de la Cámara, Agustín Gómez, Völzke, Henry, Dahm, Christina C, Dale, Caroline E, Bergmann, Manuela M, Crespo, Carlos J, van der Schouw, Yvonne T, Kaaks, Rudolf, Simons, Leon A, Lagiou, Pagona, Schoufour, Josje D, Boer, Jolanda M A, Key, Timothy J, Rodriguez, Beatriz, Moreno-Iribas, Conchi, Davidson, Karina W, Taylor, James O, Sacerdote, Carlotta, Wallace, Robert B, Quiros, J Ramon, Tumino, Rosario, Blazer, Dan G, Linneberg, Allan, Daimon, Makoto, Panico, Salvatore, Howard, Barbara, Skeie, Guri, Strandberg, Timo, Weiderpass, Elisabete, Nietert, Paul J, Psaty, Bruce M, Kromhout, Daan, Salamanca-Fernandez, Elena, Kiechl, Stefan, Krumholz, Harlan M, Grioni, Sara, Palli, Domenico, Huerta, José M, Price, Jackie, Sundström, Johan, Arriola, Larraitz, Arima, Hisatomi, Travis, Ruth C, Panagiotakos, Demosthenes B, Karakatsani, Anna, Trichopoulou, Antonia, Kühn, Tilman, Grobbee, Diederick E, Barrett-Connor, Elizabeth, van Schoor, Natasja, Boeing, Heiner, Overvad, Kim, Kauhanen, Jussi, Wareham, Nick, Langenberg, Claudia, Forouhi, Nita, Wennberg, Maria, Després, Jean-Pierre, Cushman, Mary, Cooper, Jackie A, Rodriguez, Carlos J, Sakurai, Masaru, Shaw, Jonathan E, Knuiman, Matthew, Voortman, Trudy, Meisinger, Christa, Tjønneland, Anne, Brenner, Hermann, Palmieri, Luigi, Dallongeville, Jean, Brunner, Eric J, Assmann, Gerd, Trevisan, Maurizio, Gillum, Richard F, Ford, Ian, Sattar, Naveed, Lazo, Mariana, Thompson, Simon G, Ferrari, Pietro, Leon, David A, Smith, George Davey, Peto, Richard, Jackson, Rod, Banks, Emily, Di Angelantonio, Emanuele, Danesh, John, Timo Strandberg / Principal Investigator, Department of Medicine, Clinicum, HUS Internal Medicine and Rehabilitation, APH - Personalized Medicine, APH - Aging & Later Life, and Epidemiology and Data Science

Subjects
Male, FLOATING ABSOLUTE RISK, Alcohol abuse, BLOOD-PRESSURE, 030204 cardiovascular system & hematology, Alcohol Drinking/adverse effects, 0302 clinical medicine, Cardiovascular Disease, Prospective Studies, 030212 general & internal medicine, Myocardial infarction, Prospective cohort study, Human Nutrition & Health, media_common, Medicine(all), VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Research Support, Non-U.S. Gov't, Humane Voeding & Gezondheid, Hazard ratio, Substance Abuse, Public Health, Global Health, Social Medicine and Epidemiology, ASSOCIATION, General Medicine, Middle Aged, ddc, 3. Good health, Substance abuse, Cardiovascular Diseases, CARDIOVASCULAR-DISEASE, MENDELIAN RANDOMIZATION, Female, Risk assessment, STROKE, Human, Alcohol Drinking, Lower risk, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Research Support, N.I.H., Extramural, US ADULTS, medicine, Journal Article, Life Science, Humans, media_common.cataloged_instance, CORONARY-HEART-DISEASE, ddc:610, Cardiovascular Diseases/etiology, European union, Beroendelära, METAANALYSIS, business.industry, MORTALITY, medicine.disease, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, 3121 General medicine, internal medicine and other clinical medicine, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, business, Demography
Abstract

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies.FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10–1·17), coronary disease excluding myocardial infarction (1·06, 1·00–1·11), heart failure (1·09, 1·03–1·15), fatal hypertensive disease (1·24, 1·15–1·33); and fatal aortic aneurysm (1·15, 1·03–1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91–0·97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively.INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Published
2018

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