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Cited by 515Thyroid Disorders and TreatmentsHormonal and reproductive studiesCardiovascular Function and Risk Factors

Thyroid Hormones and Cardiovascular Function and Diseases

Open access
Razvi, Salman, Jabbar, Avais, Pingitore, Alessandro, Danzi, Sara, Biondi, Bernadette, Klein, Irwin, Peeters, Robin, Zaman, Azfar +1 more·2018·Journal of the American College of Cardiology
DOI 10.1016/j.jacc.2018.02.045
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Abstract

Thyroid hormone (TH) receptors are present in the myocardium and vascular tissue, and minor alterations in TH concentration can affect cardiovascular (CV) physiology. The potential mechanisms that link CV disease with thyroid dysfunction are endothelial dysfunction, changes in blood pressure, myocardial systolic and diastolic dysfunction, and dyslipidemia. In addition, cardiac disease itself may lead to alterations in TH concentrations (notably, low triiodothyronine syndrome) that are associated with higher morbidity and mortality. Experimental data and small clinical trials have suggested a beneficial role of TH in ameliorating CV disease. The aim of this review is to provide clinicians dealing with CV conditions with an overview of the current knowledge of TH perturbations in CV disease.

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Crossref · 10.1016/j.jacc.2018.02.045

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Claims the paper makes

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  • Premisenone given

    Normal negative feedback regulation of thyroid function is disrupted by illness such as acute myocardial infarction or heart failure, producing reduced serum thyroid hormone without a rise in circulating thyroid-stimulating hormone.

    “The normal negative feedback regulation of thyroid function is disrupted by illness, including conditions such as acute myocardial infarction (AMI) or heart failure (HF), and is characterized by a reduction in serum TH without a concomitant rise in circulating TSH levels”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Thyroid hormone levels regulate thyrotropin-releasing hormone and thyroid-stimulating hormone production and release.

    “TH levels regulate TRH and TSH production and release (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Larsen, 1982, Thyroid-pituitary interaction: feedback regulation of thyrotropin secretion by thyroid hormones, N Engl J Med source

      Not checked in the free run.

  • Premisecitation

    Two subsequent trials suggested that levothyroxine in subclinical hypothyroidism reduced low-density lipoprotein cholesterol by approximately 0.3 mmol/l (11.6 mg/dl).

    “Two subsequent trials suggested that the reduction of LDL-C was approximately 0.3 mmol/l (11.6 mg/dl) (16,41).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Razvi, 2007, The beneficial effect of l-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism: randomized, crossover trial, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [41] Iqbal, 2006, Serum lipid levels in relation to serum thyroid-stimulating hormone and the effect of thyroxine treatment on serum lipid levels in subjects with subclinical hypothyroidism: the Tromsø Study, J Intern Med source

      Not checked in the free run.

  • Premisecitation

    Intravenous triiodothyronine produces similar vasodilatory effects in patients with chronic heart failure.

    “Similar effects are observed when patients with chronic HF are treated with intravenous T 3 (18).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Pingitore, 2008, Acute effects of triiodothyronine (T3) replacement therapy in patients with chronic heart failure and low-T3 syndrome: a randomized, placebo-controlled study, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Premisecitation

    Low serum triiodothyronine levels are associated with cardiac fibrosis in patients with idiopathic dilated cardiomyopathy.

    “is supported by the association of low serum T 3 levels with the presence of cardiac fibrosis in patients with idiopathic dilated cardiomyopathy (30).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Wang, 2016, Free triiodothyronine level correlates with myocardial injury and prognosis in idiopathic dilated cardiomyopathy: evidence from cardiac MRI and SPECT/PET imaging, Sci Rep source

      Not checked in the free run.

  • May combine two claims. 60
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Premisenone given

    Hyperthyroidism reduces cholesterol levels, and this reduction reverses when euthyroidism is achieved.

    “Hyperthyroidism reduces cholesterol levels, which are reversed when euthyroidism is achieved.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Some studies show that subclinical hyperthyroidism patients have increased carotid intima-media thickness and carotid artery plaques, but a recent large population-based study did not confirm this.

    “Furthermore, some studies have shown SHyper patients to have increased carotid intima-media thickness and carotid artery plaques (48,49), although this was not confirmed in a recent large, population-based study (50).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [48] Völzke, 2004, Thyroid function and carotid wall thickness, J Clin Endocrinol Metab source

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    • cites [49] Dörr, 2008, The association of thyroid function with carotid artery plaque burden and strokes in a population-based sample from a previously iodine-deficient area, Eur J Endocrinol source

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    • cites [50] Delitala, 2015, No evidence of association between subclinical thyroid disorders and common carotid intima medial thickness or atherosclerotic plaque, Nutr Metab Cardiovasc Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Thyroid hormone regulates endothelial nitric oxide production and vascular tone.

    “Several studies have shown that TH regulates endothelial nitric oxide production and vascular tone”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] Papaioannou, 2004, Treating hypothyroidism improves endothelial function, Metabolism source

      Not checked in the free run.

    • cites [15] Taddei, 2003, Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [16] Razvi, 2007, The beneficial effect of l-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism: randomized, crossover trial, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recurrent ischemia causing adverse cardiovascular events after optimal acute coronary syndrome treatment occurs in about 10% of randomized controlled trial subjects and nearly doubles in real-world registries.

    “Recurrent ischemia resulting in adverse CV events following optimal treatment for an acute coronary syndrome occurs in approximately 10% of subjects in randomized controlled trials (RCTs) (2), and this number nearly doubles in real-world registries (3).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Wallentin, 2009, Ticagrelor versus clopidogrel in patients with acute coronary syndromes, N Engl J Med source

      Not checked in the free run.

    • cites [3] Jernberg, 2015, Cardiovascular risk in post-myocardial infarction patients: nationwide real world data demonstrate the importance of a long-term perspective, Eur Heart J source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The continued progression of cardiovascular disease despite optimal prevention suggests a multifactorial cause and a need to evaluate other triggers.

    “The inexorable progress of CV disease, despite optimal guideline-based primary and secondary prevention, suggests a multifactorial etiology and the need to assess other precipitants that may exacerbate existing CV disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Hyperthyroidism causes a hyperdynamic circulation characterized by increased cardiac contractility and heart rate, increased preload, decreased systemic vascular resistance, and significantly increased cardiac output.

    “Hyperthyroidism causes a hyperdynamic circulation, characterized by increased cardiac contractility and heart rate, increased preload, and decreased systemic vascular resistance (SVR), resulting in significantly increased cardiac output.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Low thyroid function reduces cardiac function and induces morphological, molecular, and structural changes in the myocardium.

    “Low thyroid function reduces cardiac function and induces morphological, molecular, and structural changes of the myocardium.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Nongenomic thyroid hormone effects are usually receptor-independent, occur largely at the plasma membrane, and regulate ion transporter activity.

    “Nongenomic effects are usually receptor-independent and largely occur at the plasma membrane, regulating ion transporter activity (10).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Davis, 2016, Nongenomic actions of thyroid hormone, Nat Rev Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Optimal myocyte gene expression depends on serum triiodothyronine levels; if triiodothyronine falls despite normal thyroid-stimulating hormone and thyroxine, the heart expresses a hypothyroid phenotype.

    “Therefore, optimal myocyte gene expression remains dependent on serum T 3 levels, and if they fall, despite the fact that TSH and T 4 levels may be normal, the heart will express a hypothyroid phenotype.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    In mammals, thyroid hormone receptor proteins exist as alpha and beta isoforms and bind thyroid hormone response elements in promoter regions of thyroid-hormone-responsive genes.

    “In mammals, these receptor proteins exist in 2 isoforms, a and b (TRa and TRb), and bind to TH response elements in the promoter regions of THresponsive genes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Lipoprotein(a) increases in overt hypothyroidism and decreases with thyroid hormone replacement.

    “Lipoprotein(a), a more potent marker of atherogenesis, also increases in overt hypothyroidism and decreases with TH replacement (35,36).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Tzotzas, 2000, Changes in lipoprotein(a) levels in overt and subclinical hypothyroidism before and during treatment, Thyroid source

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    • cites [36] Martinez-Triguero, 1998, Effect of thyroid hormone replacement on lipoprotein(a), lipids, and apolipoproteins in subjects with hypothyroidism, Mayo Clin Proc source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hyperthyroidism can increase systolic blood pressure, but the net effect depends on the balance between increased cardiac output and decreased systemic vascular resistance.

    “Although hyperthyroidism can increase systolic blood pressure, the net effect is dependent on the balance between increased cardiac output and decreased SVR (43,44).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Danzi, 2003, Thyroid hormone and blood pressure regulation, Curr Hypertens Rep source

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    • cites [44] Ching, 1996, Cardiac hypertrophy as a result of long-term thyroxine therapy and thyrotoxicosis, Heart source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Overt hypothyroidism and hyperthyroidism produce well-documented cardiovascular and hematologic manifestations and, if untreated, can accelerate the onset of symptomatic cardiovascular disease.

    “Patients who are overtly hypo-or hyperthyroid show CV and hematologic manifestations that are well-documented, and both can, if left untreated, accelerate the onset of symptomatic CV disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A Cochrane review of six randomized controlled trials concluded that levothyroxine treatment of subclinical hypothyroidism had no overall effect on total cholesterol but suggested a trend toward reducing low-density lipoprotein cholesterol above 155 mg/dl in a subgroup analysis.

    “A Cochrane review of 6 RCTs concluded that levothyroxine treatment of SCH had no overall effect in reducing total cholesterol, but suggested a trend toward reducing LDL cholesterol (LDL-C) levels >155 mg/dl in a subgroup analysis (40).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Villar, 2007, Thyroid hormone replacement for subclinical hypothyroidism, Cochrane Database Syst Rev

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Thyroid disease, both overt and subclinical, is a global burden and is associated with increased cardiovascular disease.

    “Nevertheless, thyroid disease, both overt and subclinical, is a global burden and associated with increased CV disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hyperlipidemia in hypothyroidism is due to decreased low-density lipoprotein receptors, reduced hepatic cholesterol clearance, and decreased activity of cholesterol 7a-hydroxylase.

    “Hyperlipidemia in hypothyroidism is due to a decrease in LDL receptors, resulting in reduced cholesterol clearance from the liver and decreased activity of cholesterol 7a-hydroxylase, which is activated by TH, in breaking down cholesterol (32).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Duntas, 2002, Thyroid disease and lipids, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    TRa and TRb activate expression of positively regulated genes in the presence of triiodothyronine and repress expression in its absence.

    “TRa and TRb activate expression of positively regulated genes in the presence of T 3 and repress expression in its absence.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Patients with overt or subclinical hypothyroidism exhibit impaired endothelial function that improves with thyroid hormone replacement therapy.

    “patients with hypothyroidism (both overt and subclinical) exhibit impaired endothelial function, which improves with TH replacement therapy (14-16).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] Papaioannou, 2004, Treating hypothyroidism improves endothelial function, Metabolism source

      Not checked in the free run.

    • cites [15] Taddei, 2003, Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [16] Razvi, 2007, The beneficial effect of l-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism: randomized, crossover trial, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Low thyroid function increases peripheral vascular resistance, plasma noradrenaline concentrations, and plasma renin activity, and reduces erythropoietin.

    “Low thyroid function also increases peripheral vascular resistance, plasma noradrenaline concentrations, and plasma renin activity, and reduces erythropoietin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hypothyroidism is associated with increased low-density lipoprotein oxidation, which promotes atherogenesis and reverses with treatment.

    “Hypothyroidism is associated with increased oxidation of LDL, which promotes atherogenesis and reverses with treatment (33,34).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] Diekman, 1998, Increased oxidizability of low-density lipoproteins in hypothyroidism, J Clin Endocrinol Metab source

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    • cites [34] Costantini, 1998, Effect of thyroid function on LDL oxidation, Arterioscler Thromb Vasc Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endothelial-dependent vasodilation is lower in overtly hypothyroid and subclinical hypothyroid patients and improves with levothyroxine treatment.

    “Endothelial-dependent vasodilation is lower in overtly hypothyroid and SCH patients (51), and improves with levothyroxine treatment (15,16)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [51] Lekakis, 1997, Flow-mediated, endothelium-dependent vasodilation is impaired in subjects with hypothyroidism, borderline hypothyroidism, and high-normal serum thyrotropin (TSH) values, Thyroid source

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    • cites [15] Taddei, 2003, Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [16] Razvi, 2007, The beneficial effect of l-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism: randomized, crossover trial, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overt and subclinical hypothyroidism are associated with diastolic hypertension, impaired vascular function, and increased carotid intima hyperplasia.

    “Overt and SCH are associated with diastolic hypertension, impaired vascular function, and increased carotid intima hyperplasia (45,47).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [45] Volzke, 2009, Subclinical hyperthyroidism and blood pressure in a population-based prospective cohort study, Eur J Endocrinol source

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    • cites [47] Cai, 2011, Blood pressure levels in patients with subclinical thyroid dysfunction: a meta-analysis of cross-sectional data, Hypertens Res source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Triiodothyronine increases systolic depolarization and diastolic repolarization and decreases action potential duration, atrial myocardial refractory period, and atrial/ventricular nodal refractory period.

    “T 3 increases systolic depolarization and diastolic repolarization, and decreases the action potential duration, the refractory period of the atrial myocardium, and the atrial/ventricular nodal refractory period.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Clinical features of hyperthyroid congestive circulation include pleural effusion, hepatic congestion, and fluid retention, which can improve with diuretics and beta-blockers.

    “Clinical features of this condition are pleural effusion, hepatic congestion, and fluid retention, which can improve with diuretic agents and beta-blockers (75).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Biondi, 2012, Mechanisms in endocrinology: heart failure and thyroid dysfunction, Eur J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overt hyperthyroidism is associated with a 16% increased risk of major cardiovascular events, mainly due to a higher incidence of heart failure events.

    “Overt hyperthyroidism has been associated with 16% increased risk of major CV events, mainly due to higher incidence of HF events (74).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Selmer, 2014, Subclinical and overt thyroid dysfunction and risk of all-cause mortality and cardiovascular events: a large population study, J Clin Endocrinol Metab source

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  • May combine two claims.

    Premisecitation

    Subclinical hypothyroidism after admission for an acute cardiac problem is associated with up to a 3.6-fold increase in cardiac mortality and a 2.3-fold increase in overall death.

    “In addition, SCH after admission for an acute cardiac problem has been associated with an up to 3.6-fold increase in cardiac mortality and a 2.3-fold increase in overall death (98).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Molinaro, 2012, Persistence of mortality risk in patients with acute cardiac diseases and mild thyroid dysfunction, Am J Med Sci source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Overt hypothyroidism is prevalent in 0.2% to 2% of nonpregnant adults.

    “Overt hypothyroidism is diagnosed when serum TSH is elevated and circulating THs are low and is prevalent in 0.2% to 2% of nonpregnant adults (31,37).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Canaris, 2000, The Colorado thyroid disease prevalence study, Arch Intern Med source

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    • cites [37] Tunbridge, 1977, Lipid profiles and cardiovascular disease in the Whickham area with particular reference to thyroid failure, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The attributable risk for atrial fibrillation in these patients was 41.5% and was not altered by existing cardiovascular disease or other cardiovascular risk factors.

    “The attributable risk for AF was 41.5% in these patients, and it was not altered by the presence of existing CV disease or other CV risk factors (85).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Collet, 2012, Subclinical hyperthyroidism and the risk of coronary heart disease and mortality, Arch Intern Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hyperthyroid patients may have higher von Willebrand antigen levels than euthyroid patients, leading to enhanced platelet plug formation that decreases after treatment.

    “Hyperthyroid patients may also have higher von Willebrand antigen levels compared with euthyroid patients, leading to enhanced platelet plug formation, which decreases after treatment (60).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Homoncik, 2007, Altered platelet plug formation in hyperthyroidism and hypothyroidism, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subclinical hypothyroidism patients have decreased antithrombin III activity and increased fibrinogen, factor VII, and plasminogen activator inhibitor antigen, suggesting a potential hypercoagulable state.

    “Another study showed decreased antithrombin III activity and increased levels of fibrinogen, factor VII, and plasminogen activator inhibitor antigen in SCH patients to explain a potential hypercoagulable state (67).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Cantürk, 2003, Hemostatic system as a risk factor for cardiovascular disease in women with subclinical hypothyroidism, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both thyroid hormone deficiency and excess can alter the coagulation pathway, although the precise clinical relevance is unclear.

    “In summary, both TH deficiency and excess can alter the coagulation pathway, although the precise clinical relevance of this finding is unclear (Table 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (Table 2)

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  • May combine two claims.

    Premisecitation

    Thyroid hormone regulates the tumor suppressor p53, which is activated during acute myocardial infarction and enhances the mitochondrial apoptosis pathway.

    “TH is a regulator of the tumor suppressor p53, which is activated during AMI, enhancing the mitochondrial apoptosis pathway (21).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] de Castro, 2016, Thyroid hormones improve cardiac function and decrease expression of pro-apoptotic proteins in the heart of rats 14 days after infarction, Apoptosis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A rapid but transient decrease in serum thyroid hormone concentrations occurs immediately after acute myocardial infarction, with maximal changes between 24 and 36 hours after pain onset.

    “A rapid but transient decrease in serum TH concentrations occurs immediately after AMI (114), with maximal changes between 24 h and 36 h after the onset of pain.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] Friberg, 2002, Rapid down-regulation of thyroid hormones in acute myocardial infarction: is it cardioprotective in patients with angina?, Arch Intern Med source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Amiodarone is an iodinated benzofuran derivative that is structurally similar to thyroid hormone.

    “It is an iodinated derivative of benzofuran and is structurally similar to TH”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Each amiodarone molecule contains two iodine atoms, whereas thyroxine has four and triiodothyronine has three.

    “each molecule of the drug containing 2 iodine atoms, whereas T 4 has 4 and T 3 has 3 iodine atoms”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Experimental and observational findings contrast with the common interpretation that thyroid hormone down-regulation after acute myocardial infarction is adaptive and favorable, suggesting a potential critical role of the thyroid system in cardioprotection in acute myocardial infarction.

    “Overall, the experimental and observational findings mentioned previously are in contrast to the common interpretation that TH down-regulation after AMI is an adaptive, favorable process that helps in reducing catabolism and energy expenditure (128), and suggests the potential critical role of the thyroid system in cardioprotection in AMI.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] De Groot, 1999, Dangerous dogmas in medicine: the nonthyroidal illness syndrome, J Clin Endocrinol Metab source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Subclinical hypothyroidism and subclinical hyperthyroidism occur in 6% and 3% of heart failure patients, respectively.

    “SCH and SHyper, in contrast, occur in 6% and 3% of HF patients, respectively (129).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] Galli, 2010, The role of thyroid hormone in the pathophysiology of heart failure: clinical evidence, Heart Fail Rev source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nonthyroidal illness is common in heart failure, with a prevalence of approximately 20% to 30%.

    “As in patients with other chronic illnesses, NTI is also very common in patients with HF, with a prevalence of approximately 20% to 30% (117).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Passino, 2009, Prognostic value of combined measurement of brain natriuretic peptide and triiodothyronine in heart failure, J Card Fail source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Decreased activation and increased inactivation of thyroid hormone are major causes of acute-phase nonthyroidal illness changes, while altered hypothalamic-pituitary feedback is more important in chronic severe illness.

    “Decreased activation and increased inactivation of TH are the major causes of these changes in the acute phase of NTI, whereas an altered feedback setting at the hypothalamus-pituitary level is more important in the chronic phase of severe illness.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Histological and functional parameters document that thyroid hormone reduces myocardial damage and promotes reverse left ventricular remodeling, delaying or preventing progression to post-ischemic irreversible heart failure.

    “The net result, as documented by histological and functional parameters, is a reduction in myocardial damage and positive reverse left ventricular (LV) remodeling, resulting in a delay, or even absence, of evolution toward post-ischemic irreversible HF.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Clinical trials of thyroid hormone therapy in patients with acute myocardial infarction are ongoing.

    “Clinical trials of TH therapy in AMI patients are underway”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [142] Jabbar, 2015, Thyroxine in acute myocardial infarction (ThyrAMI) - levothyroxine in subclinical hypothyroidism post-acute myocardial infarction: study protocol for a randomised controlled trial, Trials source

      Not checked in the free run.

    • cites [143] Mourouzis, 2011, Thyroid hormone and cardiac disease: from basic concepts to clinical application, J Thyroid Res

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    p53 accumulation enhances mitochondrial dysfunction and bcl-2-like protein 4 activation, resulting in extended myocardial cell loss.

    “This favors p53 accumulation, and therefore enhances mitochondrial dysfunction and bcl-2-like protein 4 activation, resulting in extended myocardial cell loss (22).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Li, 2010, miR-30 regulates mitochondrial fission through targeting p53 and the dynamin-related protein-1 pathway, PLoS Genet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A retrospective observational study showed that levothyroxine treatment of subclinical hypothyroidism was associated with fewer ischemic heart disease events in younger individuals but not in older people.

    “Furthermore, a retrospective observational study showed that treatment of SCH with levothyroxine was associated with fewer ischemic heart disease events in younger individuals, but this was not evident in older people (102).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Razvi, 2012, Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality, Arch Intern Med source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    Low thyroid hormone levels are associated with a decreased metabolic rate.

    “As low levels of TH are associated with a decreased metabolic rate”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Thyroid-stimulating hormone may rise briefly after disease onset, but circulating thyroid-stimulating hormone usually remains low to normal despite drops in triiodothyronine and thyroxine.

    “TSH levels may rise briefly after the onset of disease, but despite the drop in serum T 3 (and in severe illness also T 4 ) levels, circulating TSH usually remains within the low to normal range.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nonthyroidal illness occurs in 15% to 20% of patients with acute myocardial infarction.

    “NTI occurs in 15% to 20% of patients with AMI (112,113).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [112] Özcan, 2014, Sick euthyroid syndrome is associated with poor prognosis in patients with ST segment elevation myocardial infarction undergoing primary percutaneous intervention, Cardiol J source

      Not checked in the free run.

    • cites [113] Li, 2011, Negative association between free triiodothyronine level and international normalized ratio in euthyroid subjects with acute myocardial infarction, Acta Pharmacol Sin source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with post-ischemic heart failure, p53-responsive microRNAs miR-192, miR-194, and miR-34a are elevated in the early phase of acute myocardial infarction and positively correlated with left ventricular diastolic dimension.

    “in patients with post-ischemic HF, p53-responsive microRNA (miR-192, miR-194, and miR-34a) levels are elevated in the early phase of AMI and are positively correlated with LV diastolic dimension (24).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Matsumoto, 2013, Circulating p53-responsive microRNAs are predictive indicators of heart failure after acute myocardial infarction, Circ Res source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Thyroid hormones contribute to cardioprotection by activating cytoprotective mechanisms, stimulating cell growth, neoangiogenesis, and metabolic adaptation.

    “THs have a role in cardioprotection due to activation of cytoprotective mechanisms, stimulation of cell growth, neoangiogenesis, and metabolic adaptation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    T3 treatment preserves hypoxia-inducible factor 1-alpha expression, whose protective effect against reperfusion injury is mediated by inhibiting mitochondrial permeability transition pore opening.

    “T 3 treatment preserves the expression of hypoxia-inducible factor 1-alpha, whose protective effect against reperfusion injury is mediated by inhibiting the mitochondrial opening of the permeability transition pore (26).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Pantos, 2007, Enhanced tolerance of the rat myocardium to ischemia and reperfusion injury early after acute myocardial infarction, Basic Res Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The acute thyroid hormone changes after acute myocardial infarction are due to increased inactivation by deiodinase 3 and decreased activation by D1 and D2.

    “These changes are due to increased inactivation of TH by the inactivating enzyme deiodinase 3 (D3) and decreased activation by D1 and D2 activity (115,116)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [115] Olivares, 2007, Thyroid function disturbance and type 3 iodothyronine deiodinase induction after myocardial infarction in rats a time course study, Endocrinology source

      Not checked in the free run.

    • cites [116] Wassen, 2002, Induction of thyroid hormone-degrading deiodinase in cardiac hypertrophy and failure, Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is no consensus on the normal upper limit of TSH, causing controversy about the definition, prevalence, and clinical significance of subclinical hypothyroidism.

    “there is a lack of consensus on what constitutes the “normal” upper limit of TSH leading to controversy on definition, prevalence and clinical significance of SCH (89).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Hamilton, 2008, Thyrotropin levels in a population with no clinical, autoantibody, or ultrasonographic evidence of thyroid disease: implications for the diagnosis of subclinical hypothyroidism, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subclinical hypothyroidism can impair vascular smooth muscle relaxation, increasing systemic vascular resistance and arterial stiffness, and alter endothelial function by reducing nitric oxide availability, without apparent clinical significance.

    “SCH can also impair relaxation of vascular smooth muscle cells, inducing increases in systemic vascular resistance and arterial stiffness, as well as changes in endothelial function by reduction of nitric oxide availability, without apparent clinical significance (92).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Owen, 2007, Thyroid disease and vascular function, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    No interventional studies of thyroid hormone replacement in acute myocardial infarction patients have been published, making a causal relationship between thyroid dysfunction and outcomes difficult to ascertain.

    “No interventional studies of TH replacement in AMI patients have been published to date, therefore making a causal relationship between thyroid dysfunction and outcomes difficult to ascertain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Echocardiographic data indicate that short-term hyperthyroidism improves left ventricular systolic function and enhances left ventricular relaxation.

    “Echocardiographic data indicate that short-term hyperthyroidism induces positive CV changes by improving LV systolic function and enhancing LV relaxation (diastolic flow velocities and isovolumic relaxation time)(72).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Palmieri, 2004, Myocardial contractility and total arterial stiffness in patients with overt hyperthyroidism: acute effects of beta1-adrenergic blockade, Eur J Endocrinol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Reported prevalence of subclinical hypothyroidism ranges from 4% to 10% of the adult population, and it is more common in women and older individuals.

    “The stated prevalence of SCH in published reports ranges from 4% to 10% of the adult population, being more common in women and older individuals (31,37).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Canaris, 2000, The Colorado thyroid disease prevalence study, Arch Intern Med source

      Not checked in the free run.

    • cites [37] Tunbridge, 1977, Lipid profiles and cardiovascular disease in the Whickham area with particular reference to thyroid failure, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Patients with subclinical hyperthyroidism may have an increased risk of atrial fibrillation, heart failure, and cardiovascular disease, similar to overt hyperthyroidism.

    “Similar to overt hyperthyroidism, patients with SHyper may have an increased risk of AF, HF, and CV disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Low T3 syndrome after acute myocardial infarction is observed in up to 1 in 5 patients, whereas subclinical hypothyroidism is observed in almost 12%.

    “Low T 3 syndrome (an isolated reduction of serum T 3 levels with normal T 4 and TSH concentrations) after AMI is observed in up to 1 in 5 patients (114), whereas SCH is observed in almost 12% (127).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [114] Friberg, 2002, Rapid down-regulation of thyroid hormones in acute myocardial infarction: is it cardioprotective in patients with angina?, Arch Intern Med source

      Not checked in the free run.

    • cites [127] Ertugrul, 2011, Prevalence of subclinical hypothyroidism among patients with acute myocardial infarction, ISRN Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a rat model of right ventricular hypertrophy and failure, D3 activity increased in the chronically overloaded right ventricle but not in the left ventricle.

    “was first shown in a rat model of right ventricular (RV) hypertrophy and failure, where D3 activity increased in the chronically overloaded RV, with no change of activity in the LVs of the same hearts (116).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] Wassen, 2002, Induction of thyroid hormone-degrading deiodinase in cardiac hypertrophy and failure, Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In moderate hypothyroidism, fibrinolytic activity is decreased and susceptibility to clot formation is increased, whereas severe hypothyroidism has increased fibrinolysis and lower tissue plasminogen activator antigen.

    “patients with moderate hypothyroidism had decreased fibrinolytic activity and were more susceptible to clot formation, whereas patients with severe hypothyroidism had increased fibrinolysis and lower tissue plasminogen activator antigen(65).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Chadarevian, 2001, Components of the fibrinolytic system are differently altered in moderate and severe hypothyroidism, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Both hyperthyroidism and hypothyroidism can occur with amiodarone therapy.

    “Both hyper-and hypothyroidism can occur with amiodarone therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The change in T3-dependent gene expression was independent of circulating T3 in mice, indicating that pathological ventricular remodeling after acute myocardial infarction causes high and stable D3 induction in cardiomyocytes, leading to a local hypothyroid condition.

    “This change in T 3 -dependent gene expression was independent of the circulating T 3 concentration in mice, showing that pathological ventricular remodeling after AMI leads to high and stable induction of D3 activity in cardiomyocytes, resulting in a subsequent local hypothyroid condition.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] Pol, 2011, Left-ventricular remodeling after myocardial infarction is associated with a cardiomyocyte-specific hypothyroid condition, Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ameliorating oxidative stress with antioxidants prevents the acute reduction of serum T3 levels in patients with acute myocardial infarction, although it is unknown whether this affects cardiac function or outcomes.

    “ameliorating oxidative stress with antioxidants prevents the acute reduction of serum T 3 levels in patients with AMI, although it is unknown if this has any effect on cardiac function or outcomes (126).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Vidart, 2014, N-acetylcysteine administration prevents nonthyroidal illness syndrome in patients with acute myocardial infarction: a randomized clinical trial, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The degree of thyroid hormone down-regulation is associated with greater impairment of cardiac function and a higher inflammatory response.

    “The degree of TH down-regulation is associated with higher impairment of cardiac function and higher inflammatory response (114,121).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [114] Friberg, 2002, Rapid down-regulation of thyroid hormones in acute myocardial infarction: is it cardioprotective in patients with angina?, Arch Intern Med source

      Not checked in the free run.

    • cites [121] Kimur, 2001, Correlation of circulating interleukin-10 with thyroid hormone in acute myocardial infarction, Res Commun Mol Pathol Pharmacol

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    D3 induction is localized to cardiomyocytes and is associated with a substantial decrease in tissue T3 concentrations and T3-dependent gene expression.

    “The induction of D3 is localized in cardiomyocytes only and is associated with a substantial decrease in tissue T 3 concentrations and T 3 -dependent gene expression (118).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] Pol, 2011, Left-ventricular remodeling after myocardial infarction is associated with a cardiomyocyte-specific hypothyroid condition, Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Studies of coagulation in overt hypothyroidism have yielded conflicting results, with two studies showing hypercoagulability and one showing increased fibrinolysis.

    “Studies investigating coagulation in overt hypothyroidism have yielded conflicting results, with 2 studies showing hypercoagulability (62,63) and 1 study showing increased fibrinolysis (64).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [62] Squizzato, 2005, Thyroid diseases and cerebrovascular disease, Stroke source

      Not checked in the free run.

    • cites [63] Erem, 2003, Blood coagulation and fibrinolytic activity in hypothyroidism, Int J Clin Pract source

      Not checked in the free run.

    • cites [64] Gullu, 2005, Effects of levothyroxine treatment on biochemical and hemostasis parameters in patients with hypothyroidism, Eur J Endocrinol source

      Not checked in the free run.

65 of 65

  • The paper relies on this without support.

    Thyroid hormone receptors are present in the myocardium and vascular tissue.

    “Thyroid hormone (TH) receptors (TRs) are present in myocardium and vascular endothelial tissues”
    “Thyroid hormone (TH) receptors are present in the myocardium and vascular tissue”

  • The paper relies on this without support.

    Thyroid function is regulated by the hypothalamic-pituitary-thyroid axis through a classic endocrine feedback loop.

    “Thyroid function is regulated by the hypothalamic-pituitary-thyroid axis via a classic endocrine feedback loop mechanism.”

  • The paper relies on this without support.

    Thyrotropin-releasing hormone is secreted by the hypothalamus and stimulates the anterior pituitary to produce thyroid-stimulating hormone, which drives the thyroid gland to release thyroid hormone.

    “Thyrotropin-releasing hormone (TRH) is secreted at the level of the hypothalamus and stimulates the anterior pituitary to produce thyroid-stimulating hormone (TSH), which, in turn, drives the thyroid gland to release TH.”

  • The paper relies on this without support.

    Amiodarone contains iodine, and a 200-mg tablet contains 500 times more iodine than the average daily requirement.

    “Amiodarone contains iodine, and a 200-mg tablet contains 500 times more iodine than the average daily requirement”
4 of 4

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?

  • Amiodarone-induced hypothyroidism is associated with adverse cardiovascular outcomes if left untreated long term.

    “nevertheless, it is important to recognise and treat as it is associated with adverse cardiovascular outcomes if left untreated long term.87”

    From Hypothyroidism (2024) · cites this paper as [87]

    The amiodarone discussion (page not provided) says amiodarone-induced hypothyroidism is treated with levothyroxine. The ‘CV CONSEQUENCES OF OVERT AND SCH’ section reports cardiovascular risks associated with hypothyroidism, but does not establish adverse long-term outcomes specifically for untreated amiodarone-induced hypothyroidism. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • 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].”

    From Thyroid and heart, a clinically relevant relationship (2021) · cites this paper as [5]

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.

  • CHD risk is called significant despite a confidence interval that includes 1

    Minor

    The stated 95% confidence interval for the CHD-events hazard ratio runs from 0.99 to 1.46. Because it includes 1, that estimate does not support the claim of a statistically significant increase in CHD events.

1 of 1

Cites

Flagged first, then by citations

3 of the 145 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Klein, 2014, Chapter 81: Endocrine disorders and cardiovascular disease, 1793

Cited by

Sorted by citations

Related

Authors
Razvi, S., Jabbar, A., Pingitore, A., Danzi, S., Biondi, B., Klein, I., Peeters, R., Zaman, A., & Iervasi, G.
Affiliations
  • Gateshead Health NHS Foundation Trust (GB)
  • Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
  • Istituto di Fisiologia Clinica (IT)
  • City University of New York (US)
  • Federico II University Hospital (IT)
  • New York University (US)
  • Erasmus MC (NL)
Corresponding author
Razvi, Salman
ORCID
Venue
Journal of the American College of Cardiology
Publisher
Elsevier BV
Published
2018-04
Volume
71
Issue
16
Pages
1781-1796
ISSN
0735-1097 (ISSN-L)
DOI
10.1016/j.jacc.2018.02.045
OpenAlex
W2800239085
Semantic Scholar
0878483096883b7de0e4d27ed98bab6d94a1b5fc
Cited by
515
References
145
Citations by year
2026: 62 · 2025: 69 · 2024: 84 · 2023: 68 · 2022: 74 · 2021: 58 · 2020: 69 · 2019: 29 · 2018: 2
FWCI
6.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American College of Cardiology (publishedVersion)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • Newcastle University ePrints (Newcastle Univesity) (cc-by-nc-nd)
Funders
National Institute for Health and Care Research (CDF-2012-05-231)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Keywords
thyroid hormones, thyroid hormone receptor, cardiovascular disease, thyroid dysfunction, endothelial dysfunction, blood pressure, diastolic dysfunction, dyslipidemia, low triiodothyronine syndrome, thyroid hormone replacement
MeSH terms
Heart Diseases, Humans, Hyperthyroidism, Risk Factors, Thyroid Hormones

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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