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Cardiovascular and neuropsychiatric outcomes associated with subclinical thyroid dysfunction: a prospective evaluation

English title Cardiovascular and neuropsychiatric outcomes associated with subclinical thyroid dysfunction: a prospective evaluation
Applicant Rodondi Nicolas
Number 138267
Funding scheme Project funding (Div. I-III)
Research institution Klinik und Poliklinik für Allgemeine Innere Medizin Inselspital
Institution of higher education University of Berne - BE
Main discipline Cardiovascular Diseases
Start/End 01.01.2012 - 30.06.2014
Approved amount 294'107.00
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All Disciplines (5)

Discipline
Cardiovascular Diseases
Clinical Endocrinology
Methods of Epidemiology and Preventive Medicine
Clinical Cardiovascular Research
Internal Medicine

Keywords (4)

Subclinical thyroid dysfunction; Prospective cohorts; Coronary Disease; Mortality

Lay Summary (English)

Lead
Lay summary

Subclinical thyroid dysfunction, a mild dysfunction of the thyroid gland, is common, particularly among older adults. Thyroid hormone acts as an essential regulatory factor in numerous physiological systems, including the vascular tree and the heart, brain (including for cognition and mood), skeletal muscle and bone. We have recently shown in JAMA that subclinical hypothyroidism was associated with an increased risk of coronary heart disease (CHD) events and CHD mortality. However, the indications for screening and for treatment of mild thyroid dysfunction are controversial, as current evidence about the risks is limited. Despite that, thyroxine for substitution of thyroid dysfunction is the 3rd most commonly used medication in the United Kingdom.

 

The main objective of this proposal is to identify and quantify the clinical risks associated with subclinical thyroid dysfunction in large prospective cohorts from our successful international collaboration (the Thyroid Studies Collaboration, with  62’000 individual participant data from 12 prospective cohorts). We will examine potential risks associated with subclinical thyroid dysfunction, such as cardiovascular events, heart failure events, stroke, atrial fibrillation, cause-specific and total mortality, as well as changes in cognitive  function, in functional capacity and in depressive symptoms.

 

This proposal will address both a gap of knowledge and a substantial clinical issue, namely the risks of subclinical thyroid dysfunction. Strengths of this proposal include the combination of analyses of large, well-characterized cohort studies, multiple mediating variables to better investigate potential mechanisms of associations with cardiovascular events and the unique international collaboration with 62,000 individual data from 12 prospective cohorts. This collaboration will have more power to answer these research questions than any single cohort worldwide and give the opportunity to analyze several subgroups that single cohorts could not examine. Given the controversy about these risks because of limited prospective cohort data, we anticipate that our study will advance scientific knowledge on these risks, which will help clarify controversy on thyroid screening and help refine a TSH threshold at which larger clinical benefits of treatment would be expected.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Comment les médecins de famille prennent-ils en charge l'hypothyroïdie infraclinique ?
Vanessa Virgini, C Baumgartner, T Bischoff, DM Haller, P Frey, T Rosenmann, TH Collet, G Sykiotis, N Pitteloud, N Rodondi (2014), Comment les médecins de famille prennent-ils en charge l'hypothyroïdie infraclinique ?, in Rev Med Suisse, 8, 526-529.
Multimorbidity and Quality of Preventive Care in Swiss University Primary Care Cohorts
Sven Streit, BR da Costa, S Weiler, TH Collet, DC Bauer, L Zimmerli, P Frey, J Cornuz, JM Gaspoz, E Battegay, E Kerr, D Aujesky, N Rodondi (2014), Multimorbidity and Quality of Preventive Care in Swiss University Primary Care Cohorts, in Plos One, 9(4), 1-7.
Subclinical Thyroid Dysfunction and Functional Capacity
Vanessa S. Virgini, LW Wijsman, N Rodondi, DC Bauer, P Kearney, J Gussekloo, W Den Elzen, JW Jukema, RGJ Westendorp, I Ford, DJ Stott, SP Mooijaart (2014), Subclinical Thyroid Dysfunction and Functional Capacity, in THYROID, 24(2), 208-214.
Behandlung bei subklinischer Hypothyreose?
Nicolas Rodondi (2013), Behandlung bei subklinischer Hypothyreose?, in Swiss Medical Forum, 13, 766.
Subclinical hypothyroidism and cardiovascular risk: how to end the controversy.
Nicolas Rodondi, Douglas C Bauer (2013), Subclinical hypothyroidism and cardiovascular risk: how to end the controversy., in J Clin Endocrinol Metab, 98(6), 2267-2269.
Subclinical thyroid dysfunction and cardiovascular outcomes among prospective cohort studies.
Gencer Baris, Collet Tinh-Hai, Virgini Vanessa, Auer Reto, Rodondi Nicolas (2013), Subclinical thyroid dysfunction and cardiovascular outcomes among prospective cohort studies., in Endocrine, metabolic & immune disorders drug targets, 13(1), 4-12.
Subclinical thyroid dysfunction and cognitive decline in old age.
Wijsman Liselotte W, de Craen Anton J M, Trompet Stella, Gussekloo Jacobijn, Stott David J, Rodondi Nicolas, Welsh Paul, Jukema J Wouter, Westendorp Rudi G J, Mooijaart Simon P (2013), Subclinical thyroid dysfunction and cognitive decline in old age., in PloS one, 8(3), 59199-59199.
Subklinische Hypothyreose: Risiken, aktuelle Empfehlungen und neue randomisierte Studie in der Schweiz
Manuel Blum, TH Collet, D Krebs, C Stettler, E Christ, V Virgini, G Sykiotis, P Frey, S Reichenbach, O Boulat, V Mooser, P Jüni, M Fiedler, D Aujesky, N Pitteloud, N Rodondi (2013), Subklinische Hypothyreose: Risiken, aktuelle Empfehlungen und neue randomisierte Studie in der Schweiz, in Swiss Med Forum, 13, 772-775.
Should we screen and treat subclinical hypothyroidism?
Vanessa S Virgini (2012), Should we screen and treat subclinical hypothyroidism?, in Rev Med Suisse, 331(8), 501-506.
Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts.
Gencer Baris, Collet Tinh-Hai, Virgini Vanessa, Bauer Douglas C, Gussekloo Jacobijn, Cappola Anne R, Nanchen David, den Elzen Wendy P J, Balmer Philippe, Luben Robert N, Iacoviello Massimo, Triggiani Vincenzo, Cornuz Jacques, Newman Anne B, Khaw Kay-Tee, Jukema J Wouter, Westendorp Rudi G J, Vittinghoff Eric, Aujesky Drahomir, Rodondi Nicolas, Thyroid Studies Collaboration (2012), Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts., in Circulation, 126(9), 1040-9.
Subclinical thyroid dysfunction and the risk of heart failure in older persons at high cardiovascular risk
David Nanchen, Jacobijn Gussekloo, Rudi G. J. Westendorp, David J. Stott, J. Wouter Jukema, Stella Trompet, Ian Ford, Paul Welsh, Naveed Sattar, Peter W. Macfarlane, Simon P. Mooijaart, Nicolas Rodondi, Anton J. M. de Craen (2012), Subclinical thyroid dysfunction and the risk of heart failure in older persons at high cardiovascular risk, in J Clin Endocrinol Metab, 97(3), 852-861.
International variation in GP treatment strategies for subclinical hypothyroidism in older adults
Wendy P. J. den Elzen, A Lefèbre–van de Fliert, V Virgini, S Mooijaart, P Kearney, N Kerse, C Mallen, V McCarthy, C Muth, T Rosemann, A Russell, H Schers, DJ Stott, M de Waal, A Warner, RGJ Westendorp, N Rodondi, J Gussekloo, International variation in GP treatment strategies for subclinical hypothyroidism in older adults, in Brit J Gen Pract.
Subclinical Thyroid Dysfunction and the Risk of Fractures: A Meta-Analysis
Wirth Christina, Blum M, da Costa BR, Baumgartner C, Collet TH, Aujesky D, Bauer DC, Rodondi N, Subclinical Thyroid Dysfunction and the Risk of Fractures: A Meta-Analysis, in Ann Intern Med.
Thyroid antibody status, subclinical hypothyroidism and the risk of coronary heart disease - An individual participant data analysis
Tinh-Hai Collet, DC Bauer, AR Cappola, BO Åsvold, S Weiler, E Vittinghoff, J Gussekloo, A Bremner, WPJ den Elzen, RMB Maciel, MPJ Vanderpump, J Cornuz, M Dörr, H Wallaschofski, AB Newman, JA Sgarbi, S Razvi, H Völzke, JP Walsh, D Aujesky, N Rodondi, Thyroid antibody status, subclinical hypothyroidism and the risk of coronary heart disease - An individual participant data analysis, in J Clin Endocrinol Metab, 1.

Collaboration

Group / person Country
Types of collaboration
Prof. R. G. J. Westendorp, Chair of Dpt of Geriatrics, University of Leiden Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. A.R. Cappola, Division of Endocrinology, University of Pennsylvania, Philadelphia United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. E. Vittinghoff, Dpt of Epidemiology and Biostatistics, University of California, San Francisco United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. D.C. Bauer, Dpt of Medicine, University of California, San Francisco United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. G. Iervasi, National Council Research Institute of Clinical Physiology, Pisa Italy (Europe)
- Publication
Prof. J.W. Jukema, Chairman "Leiden Vascular Medicine", University of Leiden Netherlands (Europe)
- Publication

Scientific events



Self-organised

Title Date Place
Meeting of the principal investigators of the international Thyroid Studies Collaboration 09.09.2013 Berne, Switzerland
1-year sabbatical in Bern: Prof. Douglas C. Bauer, expert in thyroid dysfunction, from UCSF 07.02.2012 Berne, Switzerland

Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Maladies thyroïdiennes surdiagnostiquées Le Temps Western Switzerland 2013
Media relations: print media, online media Summary in Circulation International 2012

Awards

Title Year
Best oral communication of the Swiss Society of Internal Medicine (SSMI) (1st prize) 2014
Award for Research of the Swiss Society of Internal Medicine (SSMI) for a publication in JAMA 2013
Research of the Faculty of Medicine, Lausanne, for doctoral thesis, for an article published in JAMA Intern Med 2012 2013

Associated projects

Number Title Start Funding scheme
150025 Novel biomarkers and skeletal outcomes associated with subclinical thyroid dysfunction: a prospective evaluation and impact of treatment 01.07.2014 Project funding (Div. I-III)
150025 Novel biomarkers and skeletal outcomes associated with subclinical thyroid dysfunction: a prospective evaluation and impact of treatment 01.07.2014 Project funding (Div. I-III)
116097 Impact of carotid plaque screening on smoking cessation and control of other cardiovascular risk factors: A randomized controlled trial 01.10.2007 Project funding (Div. I-III)
124112 Inflammation and acute coronary syndrome (ACS) - novel strategies for prevention and clinical management 01.02.2009 SPUM
172676 Neuropsychiatric outcomes, muscular function and exploration of metabolic pathways disrupted in subclinical thyroid dysfunction: a prospective evaluation and impact of treatment 01.07.2017 Project funding (Div. I-III)

Abstract

Background Subclinical thyroid dysfunction, defined as abnormal thyroid-stimulating hormone (TSH) and normal thyroid hormone levels, is common, particularly among older adults. It has been associated with adverse cardiovascular, psychiatric and cognitive outcomes. We have recently shown in JAMA that subclinical hypothyroidism was associated with an increased risk of coronary heart disease (CHD) events and CHD mortality.However, controversy persists on the relevance of early diagnosis and systematic screening as well as on threshold TSH levels for treatment of subclinical thyroid dysfunction. Available data show substantial limitations: 1) existing cohorts do not have serial TSH measurements to assess the potentially higher risks of persistent subclinical hypothyroidism (about 15-65% normalized TSH over time); 2) only few prospective data are available to assess other potential risks, such as heart failure, cognitive functions or psychiatric outcomes, and risks associated with subclinical hyperthyroidism. Specific aims The main objective of this proposal is to identify and quantify the clinical risks associated with subclinical thyroid dysfunction in large prospective cohorts. The specific aims are:1. In a large population-based prospective cohort (the Prosper study with 5804 older adults): A. To measure the prevalence of persistent subclinical hypothyroidism, to quantify its association with cardiovascular events and to identify the main mediating factors. B. To identify and quantify association of subclinical hypothyroidism with change in cognitive function, in functional capacity and in depressive symptoms. 2. To expand our successful international collaboration (the Thyroid Studies Collaboration, with 62’000 individual participant data from 12 prospective cohorts) to assess: A. The risks of heart failure events (HF) and stroke associated with subclinical thyroid dysfunction. B. The risks of cardiovascular events, atrial fibrillation, cause-specific and total mortality associated with subclinical hyperthyroidism.Methods We will measure thyroid function in 5804 adults aged 70-82 years from the Prosper study at baseline and at 6 months to define persistent subclinical hypothyroidism. We will examine subsequent cardiovascular events (CHD, stroke) over 11-year follow-up. For mediating factors, we will examine cardiovascular risk factors and multiple biomarkers that have been associated with increased cardiovascular risk (routinely available in the Prosper study). Other outcomes will be 3.2-year change in cognitive function, in functional capacity and in depressive symptoms. Aim 2 will take advantage of the international collaboration we have formed with 12 prospective cohorts, yielding to 62,000 individual participant data, with 580,000 person-years of follow-up. We will collect and analyze additional outcomes: HF events, atrial fibrillation, stroke, cause-specific mortality, as well as required confounders for each of these outcomes. For power issues, multiple large prospective cohorts are needed to clarify these risks and subgroups at risk. Expected value of the proposed project This proposal will address both a gap of knowledge and a substantial clinical issue, namely the risks of subclinical thyroid dysfunction. Strengths of this proposal include the combination of: 1) analyses in a large, well-characterized cohort study, including both cardiovascular and neuropsychiatric outcomes, being the first to assess clinical risks associated with persistent subclinical hypothyroidism; 2) large power given older age and high risk of participants; 3) multiple mediating variables to better investigate potential mechanisms of associations with cardiovascular events; 4) unique international collaboration with 62,000 individual data from 12 prospective cohorts to clarify controversial risks mentioned under aim 2 that need multiple cohorts. This collaboration will have more power to answer these research questions than any single cohort worldwide and give the opportunity to analyze several subgroups that single cohorts could not examine. Given the controversy about these risks because of limited prospective cohort data, we anticipate that our study will advance scientific knowledge on these risks, which will help clarify controversy on thyroid screening and help refine a TSH threshold at which larger clinical benefits of treatment would be expected.
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