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Cited by 60Thyroid Disorders and TreatmentsThyroid and Parathyroid SurgeryHormonal and reproductive studies

Thyroid and heart, a clinically relevant relationship

Open access
Corona, G., Croce, L., Sparano, C., Petrone, L., Sforza, A., Maggi, M., Chiovato, L., Rotondi, M.·2021·Journal of Endocrinological Investigation
DOI 10.1007/s40618-021-01590-9PMC PMC8572180
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Abstract

Background: Thyroid disorders, both overt and subclinical, are highly prevalent conditions in the general population. Although a clear relationship between overt thyroid dysfunctions and cardiovascular complications has long been established, data regarding subclinical thyroid dysfunction are by far more controversial. Purpose: The present review will be aimed at providing a summary of most recent evidence coming from meta-analyses regarding the complex relationship between thyroid dysfunction and cardiovascular disease. Conclusions: The review will summarize, in the first part, the physiopathological link between thyroid hormone imbalances and the cardiovascular system. In the second part the review will outline the evidence coming from meta-analyses regarding the cardiovascular risk related with both overt and subclinical thyroid dysfunctions. Particular attention will be put towards studies showing data stratified for patient’s age, TSH levels and pre-existing cardiovascular disease. Finally, an overview regarding the effects of specific therapy for subclinical thyroid diseases in terms of amelioration of cardiovascular outcomes will be included.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes meta-analytic evidence linking thyroid dysfunction to cardiovascular disease, covering pathophysiological mechanisms and outcomes for overt and subclinical hypo- and hyperthyroidism. It concludes that overt thyroid dysfunction clearly raises cardiovascular morbidity and mortality, while the subclinical picture is more controversial and patient age is a major determinant of whether treatment helps.

Key findings

  • Overt hypothyroidism: a meta-analysis of 55 studies (1,898,314 subjects) found increased risk of myocardial ischemia (13%), myocardial infarction (15%), arrhythmias (96%) and overall mortality (25%) versus euthyroidism.
  • Overt hyperthyroidism: one meta-analysis (7 studies, 31,138 subjects) reported increased overall mortality by 13% and cardiovascular mortality by 21%; a more recent meta-analysis (37 studies, 113,393 hyperthyroid subjects) found increased risk of ischemic heart disease, stroke and cardiovascular mortality.
  • Subclinical hypothyroidism (SC-HT): 11 meta-analyses since 2006 (4–37 studies; 2,116–1,473,648 subjects) mostly report increased coronary events and CV mortality, with risk most evident in younger subjects and at TSH > 10 mU/L; MACE risk was significant only in subjects < 65 years, and a meta-analysis of four prospective cohorts in subjects > 80 years found no association with all-cause mortality.
  • Subclinical hyperthyroidism (SC-HPT): 9 meta-analyses since 2006 (4–17 studies; 2,116–71,808 subjects) show close association with atrial fibrillation and congestive heart failure (especially grade 2), and increased CV mortality/morbidity, with risk greater in older subjects and attenuated after adjustment for confounders; no relationship with stroke was observed.
  • Levothyroxine (LT4) therapy in SC-HT: a meta-analysis of 5 observational studies and 2 RCTs (21,055 patients) found reduced all-cause mortality (RR = 0.50, 95% CI 0.29–0.85, p = 0.011) and cardiovascular mortality (RR = 0.54, 95% CI 0.37–0.80, p = 0.002) in patients younger than 65 years, but not in older patients.

Methods

  • Design: comprehensive narrative review of published meta-analyses on thyroid dysfunction and cardiovascular function/risk.
  • Data sources: Medline, Embase and Cochrane searches using MeSH and free-text terms for thyroid and cardiovascular diseases; publications from January 1, 1969 to January 15, 2021; meta-analytic data preferred when available.
  • Analysis: narrative synthesis of meta-analyses, with attention to studies stratified by patient age, TSH levels and pre-existing cardiovascular disease, plus an overview of therapy effects on cardiovascular outcomes.

Limitations

  • The paper states no formal limitations section; it is a narrative review rather than a systematic review with its own quantitative synthesis.
  • Evident from the text: the authors repeatedly note that data on subclinical thyroid dysfunction are "controversial" and that overall mortality findings are "conflicting" and require further studies; the evidence base is heterogeneous (meta-analyses varying from 4 to 37 studies and from 2,116 to 1,473,648 subjects, with differing TSH cut-offs and follow-up).
  • Evident from the text: no RCTs with cardiovascular mortality and morbidity as the primary endpoint after LT4 therapy have been published, so therapeutic conclusions rest on indirect evidence from meta-analyses and observational registries.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s40618-021-01590-9

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 56 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    The association between subclinical hypothyroidism and increased risk for cardiovascular morbidity and mortality appears to be rather consistently reported, particularly by meta-analyses involving a larger number of studies, even after correction for conventional cardiovascular risk factors.

    “Overall, it is interesting to underline that the association between SC-HT and increased risk for CV morbidity and mortality appears to be rather consistently reported, particularly by those meta-analyses involving a larger number of studies, even after correction for conventional CV risk factors.”
    Quote in the paperSubstantial claim
  • Findingnone given

    Most studies reported a relationship between subclinical hypothyroidism and increased risk of coronary events and cardiovascular mortality.

    “Most studies reported a relationship between SC-HT and increased risk of coronary events and CV mortality (Fig. 1, Panels A–C).”
    Quote in the paperSubstantial claim
  • Findingnone given

    Severe subclinical hypothyroidism (TSH > 10 mU/L) is associated with increased risk of congestive heart failure.

    “The presence of severe SC-HT (i.e., as defined by circulating TSH levels > 10 mU/L) would also be associated with an increased risk of congestive heart failure without a relationship between SC-HT and AF (Fig. 1, Panel B).”
    Quote in the paperSubstantial claim
  • Findingcitation

    The association between subclinical hypothyroidism and increased risk of MACE was significant only for younger subjects (<65 years) with higher cardiovascular risk, unlike older individuals (>65 years).

    “Furthermore, the association between SC-HT and increased risk of MACE was found to be significant only for younger subjects (< 65 years) with a higher CV risk, unlike older individuals (> 65 years) (Fig. 1, Panel B) [25].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Moon S, Kim MJ, Yu JM, Yoo HJ, Park YJ (2018) Subclinical hypothyroidism and the risk of cardiovascular disease and all-cause mortality: a meta-analysis of prospective cohort studies. Thyroid 28(9):1101–1110. https://doi.org/10.1089/thy.2017.0414 source

      Not checked in the free run.

  • Findingcitation

    The association between subclinical hypothyroidism and increased risk of coronary events and cardiovascular mortality was confirmed by the only study reporting MACE.

    “This association was also confirmed by the only study reporting the association between SH and the most validated cardiovascular outcome (MACE; Fig. 1, Panel B).”
    Quote in the paperSubstantial claim
  • May combine two claims. 12
  • The quote only partly states this claim. 3

  • May combine two claims.

    Findingreasoning

    The risk of cardiovascular events associated with subclinical hypothyroidism seems particularly evident in younger subjects and when TSH values > 10 mU/L are considered.

    “The risk seems particularly evident in younger subjects and when TSH values > 10 mU/L are considered (Fig. 1, Panel B).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    There is no relationship between subclinical hypothyroidism and atrial fibrillation.

    “The presence of severe SC-HT (i.e., as defined by circulating TSH levels > 10 mU/L) would also be associated with an increased risk of congestive heart failure without a relationship between SC-HT and AF (Fig. 1, Panel B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The relationship between subclinical hypothyroidism and overall mortality is conflicting, although the two meta-analyses with larger number of studies suggest increased risk in younger subjects.

    “The relationship between SC-HT and overall mortality is more conflicting although the two meta-analyses [11, 25] which considered a larger number of studies suggest an increased risk in younger subjects (Fig. 1, Panels A and C).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Ning Y, Cheng YJ, Liu LJ et al (2017) What is the association of hypothyroidism with risks of cardiovascular events and mortality? A meta-analysis of 55 cohort studies involving 1,898,314 participants. BMC Med 15(1):21. https://doi.org/10.1186/s12916-017-0777-9 source

      Not checked in the free run.

    • cites [25] Moon S, Kim MJ, Yu JM, Yoo HJ, Park YJ (2018) Subclinical hypothyroidism and the risk of cardiovascular disease and all-cause mortality: a meta-analysis of prospective cohort studies. Thyroid 28(9):1101–1110. https://doi.org/10.1089/thy.2017.0414 source

      Not checked in the free run.

  • The quote only partly states this claim.

    Findingown data

    The cardiovascular risk in subclinical hyperthyroidism would likely be attenuated by adjustment for confounding risk factors.

    “Overall, unlike what has been observed in SC-HT, the CV risk appears to be greater in older rather than younger subjects and it would likely be attenuated by the adjustment for confounding risk factors (Fig. 2, Panels B and C).”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    At the cardiac level, stimulation of β-type thyroid-hormone receptors up-regulates calcium-dependent ATPase pumps of the endoplasmic reticulum and reduces expression of Phospholamban, resulting in increased myocardial relaxation and a positive inotropic effect.

    “At the cardiac level, stimulation of the β-type thyroid-hormone receptors determines an up-regulation of the calcium-dependent ATPase pumps of the endoplasmic reticulum and a reduced expression of the Phospholamban protein resulting in an inhibitory action.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Klein I, Danzi S (2007) Thyroid disease and the heart. Circulation 116(15):1725–1735. https://doi.org/10.1161/CIRCULATIONAHA.106.678326 source

      Not checked in the free run.

    • cites [6] Klein I, Danzi S (2016) Thyroid disease and the heart. Curr Probl Cardiol 41(2):65–92. https://doi.org/10.1016/j.cpcardiol.2015.04.002 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Thyroid hormones exert a direct action at the cardiac level through genomic and non-genomic effects, contributing to regulation of cardiac function and cardiovascular hemodynamics.

    “Thyroid hormones exert a direct action at the cardiac level through the combination of genomic and non-genomic effects, ultimately contributing to the regulation of cardiac function and CV hemodynamics [5].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Razvi S, Jabbar A, Pingitore A et al (2018) Thyroid hormones and cardiovascular function and diseases. J Am Coll Cardiol 71(16):1781–1796. https://doi.org/10.1016/j.jacc.2018.02.045 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypothyroidism reduces activity of the myocardial pacemaker and lengthens QT intervals, which can lead to advanced atrio-ventricular blocks or torsades-de-pointes resulting in ventricular tachycardia.

    “The presence of hypothyroidism also involves a reduction in the activity of the myocardial pacemaker and a lengthening of the QT intervals which can lead to the appearance of advanced atrio-ventricular blocks or torsades-de-pointes resulting in ventricular tachycardia [1, 3].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Klein I, Danzi S (2007) Thyroid disease and the heart. Circulation 116(15):1725–1735. https://doi.org/10.1161/CIRCULATIONAHA.106.678326 source

      Not checked in the free run.

    • cites [3] Garber JR, Cobin RH, Gharib H et al (2012) Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract 18(6):988–1028. https://doi.org/10.4158/EP12280.GL source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At the renal level, reduced perfusion from peripheral vasodilation activates the renin-angiotensin-aldosterone system, with sodium-retentive action and increased circulating volume.

    “At the renal level, this effect leads to a reduced perfusion with consequent activation of the renin–angiotensin–aldosterone system (to which a direct effect of T3 via thyroid β-1 receptors probably also contributes) with a sodium-retentive action and an increase in circulating volume [1, 6].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Klein I, Danzi S (2007) Thyroid disease and the heart. Circulation 116(15):1725–1735. https://doi.org/10.1161/CIRCULATIONAHA.106.678326 source

      Not checked in the free run.

    • cites [6] Klein I, Danzi S (2016) Thyroid disease and the heart. Curr Probl Cardiol 41(2):65–92. https://doi.org/10.1016/j.cpcardiol.2015.04.002 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    T3 induces an increase in expression of β1-adrenergic receptors on myocardiocytes, increasing myocardial sensitivity to catecholamines, while simultaneously inhibiting cardiac expression of catalytic isoforms of adenylate-cyclase, keeping the endocellular response unchanged.

    “Indeed, T3 induces an increase in the expression of β1-adrenergic receptors on myocardiocytes, increasing myocardial sensitivity to the action of catecholamines, as it simultaneously inhibits the cardiac expression of the catalytic isoforms of adenylate–cyclase, keeping the endocellular response unchanged [1, 6].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Klein I, Danzi S (2007) Thyroid disease and the heart. Circulation 116(15):1725–1735. https://doi.org/10.1161/CIRCULATIONAHA.106.678326 source

      Not checked in the free run.

    • cites [6] Klein I, Danzi S (2016) Thyroid disease and the heart. Curr Probl Cardiol 41(2):65–92. https://doi.org/10.1016/j.cpcardiol.2015.04.002 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overt hypothyroidism is often associated with early diastolic dysfunction, which together with diastolic hypertension and/or other risk factors can lead to difficult-to-treat heart failure.

    “Echocardiographic studies have shown that overt hypothyroidism is often associated with early diastolic dysfunction which, together with the frequent occurrence of diastolic hypertension and/or other risk factors in these patients, can lead to difficult-to-treat heart failure [1, 3].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Klein I, Danzi S (2007) Thyroid disease and the heart. Circulation 116(15):1725–1735. https://doi.org/10.1161/CIRCULATIONAHA.106.678326 source

      Not checked in the free run.

    • cites [3] Garber JR, Cobin RH, Gharib H et al (2012) Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract 18(6):988–1028. https://doi.org/10.4158/EP12280.GL source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with overt hyperthyroidism experience atrial fibrillation at a rate ranging from 10 to 25%, with higher percentages in males over 60 years and in those with higher free T4 values.

    “Patients with overt hyperthyroidism, at a rate ranging from 10 to 25%, experience atrial fibrillation (AF) with even higher percentages in males over 60 years of age and in those with higher free T4 (FT4) values.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Klein I, Danzi S (2007) Thyroid disease and the heart. Circulation 116(15):1725–1735. https://doi.org/10.1161/CIRCULATIONAHA.106.678326 source

      Not checked in the free run.

    • cites [6] Klein I, Danzi S (2016) Thyroid disease and the heart. Curr Probl Cardiol 41(2):65–92. https://doi.org/10.1016/j.cpcardiol.2015.04.002 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypothyroidism negatively impacts glucose and lipid metabolism, possibly favoring insulin resistance and hypercholesterolemia, which may be at least partly reverted by replacement therapy.

    “Finally, the presence of hypothyroidism negatively impacts glucose and lipid metabolism possibly favoring the onset of insulin resistance and hypercholesterolemia which may, at least in part, be reverted by replacement therapy [9, 10].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Han C, He X, Xia X et al (2015) Subclinical hypothyroidism and type 2 diabetes: a systematic review and meta-analysis. PLoS ONE 10(8):e0135233. https://doi.org/10.1371/journal.pone.0135233 source

      Not checked in the free run.

    • cites [10] Li X, Wang Y, Guan Q, Zhao J, Gao L (2017) The lipid-lowering effect of levothyroxine in patients with subclinical hypothyroidism: a systematic review and meta-analysis of randomized controlled trials. Clin Endocrinol (Oxf) 87(1):1–9. https://doi.org/10.1111/cen.13338 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Levothyroxine therapy is associated with a lower number of coronary ischemic events in young subjects with subclinical hypothyroidism (40-70 years) but not in older ones.

    “An analysis of the United Kingdom general practitioner registry showed that LT4 therapy is associated with a lower number of coronary ischemic events in young subjects with SC-HT (40–70 years) but not in older ones [33].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Razvi S, Weaver JU, Butler TJ, Pearce SH (2012) Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch Intern Med 172(10):811–817. https://doi.org/10.1001/archinternmed.2012.1159 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Levothyroxine therapy is not associated with reduction in all-cause or cardiovascular mortality in older patients with subclinical hypothyroidism.

    “The results showed that LT4 therapy was associated with a significant reduction in all-cause (RR = 0.50, CI 0.29–0.85, p = 0.011) and cardiovascular (RR = 0.54, 95% CI 0.37–0.80, p = 0.002) mortality in patients younger than 65 years, but not in older patients [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Peng CC, Huang HK, Wu BB, Chang RH, Tu YK, Munir KM (2021) Association of thyroid hormone therapy with mortality in subclinical hypothyroidism: a systematic review and meta-analysis. J Clin Endocrinol Metab 106(1):292–303. https://doi.org/10.1210/clinem/dgaa777 source

      Not checked in the free run.

14 of 14

  • The paper relies on this without support.

    The meta-analyses included in this review are of sufficient methodological quality and their pooled estimates are valid for the populations studied.

    “When available, meta-analytic data were preferred.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • A comprehensive meta-analysis including 55 studies and 1,898,314 subjects concluded that overt hypothyroidism is associated with increased risk of myocardial ischemia (13%), myocardial infarction (15%), arrhythmias (96%) and overall mortality (25%) compared to euthyroidism.

    “Recently, a comprehensive meta-analysis including 55 studies and a total of 1,898,314 subjects, concluded that the presence of overt hypothyroidism is associated with an increased risk of myocardial ischemia (13%), myocardial infarction (15%), arrhythmias (96%) and overall mortality (25%) when compared to euthyroidism [47].”

    From Risks of suboptimal and excessive thyroid hormone replacement across ages (2023) · cites this paper as [47]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Table 2 gives a hypothyroid-range cutoff for subclinical hyperthyroidism

    Minor

    The paper defines subclinical hyperthyroidism using TSH at or below 0.45 mU/L, but Table 2 gives a 4-5 mU/L cutoff for one analysis under subclinical hyperthyroidism.

  • Subclinical hyperthyroidism patient-count range excludes a listed analysis

    Minor

    The stated maximum is 71,808 subjects, whereas Table 2 lists a meta-analysis with 1,626,005.

  • Subclinical hyperthyroidism study-count range excludes a listed analysis

    Minor

    The text says these meta-analyses included at most 17 studies, but Table 2 lists one with 37.

3 of 3

Cites

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Related

Authors
Corona, G., Croce, L., Sparano, C., Petrone, L., Sforza, A., Maggi, M., Chiovato, L., & Rotondi, M.
Affiliations
  • Azienda USL di Bologna (IT)
  • University of Pavia (IT)
  • University of Florence (IT)
Corresponding author
Rotondi, M.
ORCID
Venue
Journal of Endocrinological Investigation
Publisher
Springer Science and Business Media LLC
Published
2021-05-25
Volume
44
Issue
12
Pages
2535-2544
ISSN
  • 0391-4097 (ISSN-L)
  • 1720-8386
DOI
10.1007/s40618-021-01590-9
PMC
PMC8572180
OpenAlex
W3164410902
Semantic Scholar
c974fd925ff6b5d1e480ea6a8a7786b491032988
Cited by
60
References
42
Citations by year
2026: 9 · 2025: 5 · 2024: 17 · 2023: 16 · 2022: 11 · 2021: 2
FWCI
1.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Endocrinological Investigation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Florence Research (University of Florence) (submittedVersion, other-oa)
Funders
Università degli Studi di Pavia
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
Keywords
thyroid dysfunction, subclinical hypothyroidism, overt hypothyroidism, cardiovascular disease, cardiovascular risk, thyroid hormones, thyroid-stimulating hormone, thyroid hormone replacement, meta-analysis
MeSH terms
Heart Disease Risk Factors, Cardiovascular Diseases, Humans, Thyroid Diseases, Thyroid Hormones

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