Subclinical Thyroid Dysfunction and the Risk of Heart Failure Events: An Individual Participant Data Analysis From 6 Prospective Cohorts
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Background—: American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events. Methods and Results—: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of heart failure events. Individual data on 25 390 participants with 216 248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L, subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L, and subclinical hyperthyroidism as TSH <0.45 mIU/L, the last two with normal free thyroxine levels. Among 25 390 participants, 2068 (8.1%) had subclinical hypothyroidism and 648 (2.6%) had subclinical hyperthyroidism. In age- and sex-adjusted analyses, risks of heart failure events were increased with both higher and lower TSH levels ( P for quadratic pattern <0.01); the hazard ratio was 1.01 (95% confidence interval, 0.81–1.26) for TSH of 4.5 to 6.9 mIU/L, 1.65 (95% confidence interval, 0.84–3.23) for TSH of 7.0 to 9.9 mIU/L, 1.86 (95% confidence interval, 1.27–2.72) for TSH of 10.0 to 19.9 mIU/L ( P for trend <0.01) and 1.31 (95% confidence interval, 0.88–1.95) for TSH of 0.10 to 0.44 mIU/L and 1.94 (95% confidence interval, 1.01–3.72) for TSH <0.10 mIU/L ( P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors. Conclusion—: Risks of heart failure events were increased with both higher and lower TSH levels, particularly for TSH ≥10 and <0.10 mIU/L.
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The risk of heart failure events did not differ after further adjustments for potential confounding risk factors and after the exclusion of patients with preexisting heart failure or atrial fibrillation.
“The risk of HF events did not differ after further adjustments for potential confounding risk factors and after the exclusion of patients with preexisting HF or AF [75] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [75]
The Results (page unavailable) say that HF-event risks were similar after further adjustment and remained elevated for participants with TSH ≥10.0 mIU/L after excluding those with preexisting AF. But after excluding the Bari study, whose participants all had preexisting HF, the hazard ratio decreased to 1.62. The claim omits the TSH qualification and overstates the finding as no difference after both exclusions. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAmong 648 participants with subclinical hyperthyroidism, the hazard ratio for heart failure events was significantly increased during a median follow-up of 10.4 years in age- and sex-adjusted analyses.
“Among the 648 participants with SHyper, the HR for HF events was significantly increased during a median follow-up of 10.4 years in ageand sex-adjusted analyses, although a limited number of participants were <50 years.”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [75]
The Results report 648 participants with subclinical hyperthyroidism and a median follow-up of 10.4 years for the full sample. In age- and gender-adjusted analyses, the heart-failure hazard ratio was significantly elevated for the TSH <0.10 mIU/L subgroup, but not for the TSH 0.10–0.44 mIU/L subgroup; the cited passages do not establish a significant increase for all 648 participants. The Discussion also notes limited power in analyses of participants younger than 50. (LLM, conf=0.88)
Experimental — accuracy not yet measuredData from all available prospective cohort studies demonstrate that SHyper is associated with an increased risk of total mortality, CHD mortality and incident AF.
“Data from all the available prospective cohort studies demonstrate that SHyper is associated with an increased risk of total mortality, CHD mortality and incident AF.”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [75]
The Background (page unavailable) links subclinical hyperthyroidism with CHD events and mortality, and the Discussion (page unavailable) reports increased CHD mortality and atrial fibrillation risk. The copy does not specifically establish increased total mortality or say that all available prospective cohorts demonstrated these three outcomes; its pooled cohort analysis concerns heart failure events. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThese meta-analyses performed sensitivity analyses excluding participants with missing values of FT4 and total FT3, and used the I2 statistic to assess heterogeneity across studies.
“Moreover, these meta-analyses performed sensitivity analyses excluding participants with missing values of FT 4 and total FT 3 , and used the I 2 statistic to assess heterogeneity across studies.”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [75]
The Methods sections (pages not provided) state that participants with missing FT4 values were excluded in sensitivity analyses and that the I² statistic was used to assess heterogeneity across studies. They do not report excluding participants with missing FT3 values; the Discussion instead describes sensitivity analyses excluding those with abnormal FT3. (LLM, conf=0.89)
Experimental — accuracy not yet measuredThree recent meta-analyses provide evidence, based also on IPD data, for treating SHyper with undetectable TSH because of an excess risk of total mortality, CHD mortality, HF, incident AF and fractures among adults with grade 2 SHyper.
“Three recent meta-analyses provide evidence, based also on IPD data, for treating SHyper with undetectable TSH because of an excess risk of total mortality, CHD mortality, HF, incident AF and fractures among adults with grade 2 SHyper [71,75,108,109] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [75]
The Results and Discussion (pages unavailable) report an individual-participant-data analysis finding increased heart-failure risk with TSH <0.10 mIU/L (HR 1.94, 95% CI 1.01–3.72), supporting the heart-failure portion of the claim. This paper does not establish excess risk for all the other listed outcomes or that treating subclinical hyperthyroidism improves them; its Discussion cautions against basing treatment decisions on observational findings alone. (LLM, conf=0.88)
Experimental — accuracy not yet measured
These meta-analyses do not show evidence that treatment is effective in improving the risks associated with untreated SHyper.
“Although these meta-analyses do not show evidence that treatment is effective in improving the risks associated with untreated SHyper, they demonstrate that SHyper is a potentially life-threatening condition.”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [75]
The Background (page unavailable) says no randomized controlled trials had evaluated whether treating subclinical thyroid dysfunction affects clinical heart-failure outcomes, and that evidence for treatment is limited. This supports the absence of demonstrated treatment benefit for heart-failure events, but the claim extends that absence to the risks of untreated subclinical hyperthyroidism generally. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe risk of heart failure was much higher in participants with grade 2 subclinical hyperthyroidism (HR 1.94; 95% CI 1.01-3.72) than in those with grade 1 subclinical hyperthyroidism (HR 1.31; 95% CI 0.88-1.95; p for trend 0.047).
“The risk of HF was much higher in participants with grade 2 SHyper (HR = 1.94; 95% CI: 1.01-3.72)than in those with grade 1 SHyper (HR = 1.31; 95% CI: 0.88-1.95;p for trend across lower TSH categories 0.047).”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [75]
Two recent meta-analyses included IPD from all available prospective studies on the cardiovascular outcome of SHyper.
“The task force recognized that two recent meta-analyses have provided relevant information on the cardiovascular outcome of SHyper because they included IPD from all the available prospective studies [71,75] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [75]
The risks of CHD mortality and AF are greater among adults with grade 2 SHyper.
“The risks of CHD mortality and AF are greater among adults with grade 2 SHyper [71,75] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [75]
These meta-analyses assessed baseline cardiovascular risk factors, pre-existing CVD and thyroid-altering medication use, and stratified the analysis by age, sex, race and TSH categories.
“They assessed baseline cardiovascular risk factors, pre-existing cardiovascular disease (CVD) and thyroid-altering medication use, and stratified the analysis by age, sex, race and TSH categories [71,75] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [75]
These meta-analyses demonstrate that SHyper is a potentially life-threatening condition.
“Although these meta-analyses do not show evidence that treatment is effective in improving the risks associated with untreated SHyper, they demonstrate that SHyper is a potentially life-threatening condition.”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [75]
Recent individual patient meta-analysis by the Thyroid Studies Collaboration did not find higher risk of cardiovascular disease and all-cause mortality among adults with subclinical hypothyroidism compared with those with euthyroidism.
“Recent individual patient meta-analysis by the Thyroid Studies Collaboration8,9,10,11 did not find higher risk of CVD and all-cause mortality among adults with subclinical hypothyroidism compared with those with euthyroidism”
From Association of subclinical hypothyroidism and cardiovascular disease with mortality (2020) · cites this paper as [9]
The most recent data indicate that SH subjects appear to be at particular risk for the development of heart failure, especially older subjects and those with lower TSH levels.
“The most recent data indicate that SH subjects appear to be at particular risk for the development of heart failure (381,388,392), especially older subjects (381,392) and those with lower TSH levels (392).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [392]
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Self-citationSubclinical hypothyroidism: Should we treat?
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2026 ESC Guidelines for the management of heart failure
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Self-citation
- Authors
- Gencer, B., Collet, T.-H., Virgini, V., Bauer, D. C., Gussekloo, J., Cappola, A. R., Nanchen, D., den Elzen, W. P. J., Balmer, P., Luben, R. N., Iacoviello, M., Triggiani, V., Cornuz, J., Newman, A. B., Khaw, K.-T., Jukema, J. W., Westendorp, R. G. J., Vittinghoff, E., Aujesky, D., & Rodondi, N.
- Affiliations
- From the Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland (B.G., T.-H.C., D.N., P.B., J.C.); Department of General Internal Medicine, Bern University Hospital, Bern, Switzerland (V.V., D.A., N.R.); Departments of Epidemiology and Biostatistics (D.C.B., E.V.) and Medicine (D.C.B.), University of California San Francisco; Departments of Public Health and Primary Care (J.G., W.P.J.d.E.), Cardiology (J.W.J.), and Gerontology and Geriatrics (R.G.J.W.),...
- University of Pittsburgh (US)
- ORCID
- Venue
- Circulation
- Published
- 2012-08-28
- Volume
- 126
- Issue
- 9
- Pages
- 1040-1049
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC3884576
- OpenAlex
- W2000333200
- Cited by
- 517
- References
- 41
- Citations by year
- 2026: 23 · 2025: 28 · 2024: 36 · 2023: 61 · 2022: 34 · 2021: 48 · 2020: 44 · 2019: 39 · 2018: 37 · 2017: 30 · 2016: 26 · 2015: 39 · 2014: 31 · 2013: 32 · 2012: 7
- FWCI
- 27.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Archive ouverte UNIGE (University of Geneva) (acceptedVersion, other-oa)
- Leiden Repository (Leiden University) (submittedVersion)
- IRIS (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- BORIS (University Library Bern) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion, other-oa)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- National Science Foundation
- American Heart Association
- Bristol-Myers Squibb
- University of Pittsburgh (P30-AG024827)
- Cancer Research UK
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SPUM 33CM30-124 112, 15103, 138267, 20098, 124112, 320030)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (050.060.810, 05040202)
- National Institutes of Health (N01-AG-6-2103, n01hc085082-026, n01hc085081-021, n01ag062101-007, n01hc045133-001, n01hc085079-024, n01hc015103-009, n01hc085084-005, n01ag062103-006, n01hc085085-011, n01hc085083-027, n01hc085080-026, N01‐AG‐6‐2106, n01ag062106-007, n01hc085086-022, N01-AG-6-2101, n01hc075150-004, n01hc035129-010, n01hc055222-001, N01HC85086, AG-027058, AG 20098, N01HC85079, HL-075366, AG-023629, N01-HC-75150, N01HC-35129, N01HC-15103, N01-HC-45133, HL080295)
- Medical Research Council
- National Institute on Aging (N01‐AG‐6–2101, R01AG028050, R56AG023629, R01AG032317, R01AG020098, R01-AG-15928, R01 AG20098, AG023629, AG027058, N01AG62106, R01AG023629, R01AG015928, N01-AG-62103, R01AG027058, AG-032317, P30AG024827)
- National Heart, Lung, and Blood Institute (N01-HC-85081, N01HC85085, N01 HC085086, AG-023629, N01HC-85083, AG-027058, R01-NR012459, N01HC15103, N01 HC085079, N01HC85082, N01HC‐75150, N01 HC85086, AG-20098, N01 HC035129, HL-075366, N01HC85080, N01AG62101, N01 HC015103, N01HC80007, N01 HC55222, R01HL075366, N01‐HC‐45133, N01AG62106, U01HL080295, N01 HC055222, R01 HL, N01AG62103, AG-15928, HL080295, N01 HC075150, N01 HC045133, N01-HC85079, N01-HC85084, N01HC35129)
- National Institute of Nursing Research (N01-AG-6–2101, N01-AG-6-2103, N01-AG-6–2106, NR012459, R01NR012459)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K24AR051895)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- subclinical thyroid dysfunction, heart failure, thyroid-stimulating hormone, subclinical hypothyroidism, subclinical hyperthyroidism, TSH levels, heart failure risk, euthyroidism, free thyroxine, cardiovascular risk factors, individual patient data meta-analysis, prospective cohort, thyroid function tests, heart failure exacerbation, heart failure hospitalization, heart failure mortality, heart failure readmission
- MeSH terms
- Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Heart Failure, Humans, Hypothyroidism, Male, Middle Aged, Prospective Studies, Risk, Risk Factors, Sensitivity and Specificity, Thyrotropin, Thyroxine, Comorbidity
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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