Thyroid Hormones and Cardiovascular Function and Diseases

In the paper

“Hyperthyroidism reduces cholesterol levels, which are reversed when euthyroidism is achieved.”

In the paper

“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).”

What the sources say

• Not checked yetcites [48] Völzke, 2004, Thyroid function and carotid wall thickness, J Clin Endocrinol Metab source
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“Several studies have shown that TH regulates endothelial nitric oxide production and vascular tone”

What the sources say

• Not checked yetcites [14] Papaioannou, 2004, Treating hypothyroidism improves endothelial function, Metabolism source
• Not checked yetcites [15] Taddei, 2003, Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy, J Clin Endocrinol Metab source
• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [2] Wallentin, 2009, Ticagrelor versus clopidogrel in patients with acute coronary syndromes, N Engl J Med source
• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“Nongenomic effects are usually receptor-independent and largely occur at the plasma membrane, regulating ion transporter activity (10).”

What the sources say

• Not checked yetcites [10] Davis, 2016, Nongenomic actions of thyroid hormone, Nat Rev Endocrinol source

In the paper

“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.”

In the paper

“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.”

In the paper

“Lipoprotein(a), a more potent marker of atherogenesis, also increases in overt hypothyroidism and decreases with TH replacement (35,36).”

What the sources say

• Not checked yetcites [35] Tzotzas, 2000, Changes in lipoprotein(a) levels in overt and subclinical hypothyroidism before and during treatment, Thyroid source
• Not checked yetcites [36] Martinez-Triguero, 1998, Effect of thyroid hormone replacement on lipoprotein(a), lipids, and apolipoproteins in subjects with hypothyroidism, Mayo Clin Proc source

In the paper

“Although hyperthyroidism can increase systolic blood pressure, the net effect is dependent on the balance between increased cardiac output and decreased SVR (43,44).”

What the sources say

• Not checked yetcites [43] Danzi, 2003, Thyroid hormone and blood pressure regulation, Curr Hypertens Rep source
• Not checked yetcites [44] Ching, 1996, Cardiac hypertrophy as a result of long-term thyroxine therapy and thyrotoxicosis, Heart source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [40] Villar, 2007, Thyroid hormone replacement for subclinical hypothyroidism, Cochrane Database Syst Rev

In the paper

“Nevertheless, thyroid disease, both overt and subclinical, is a global burden and associated with increased CV disease.”

In the paper

“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).”

What the sources say

• Not checked yetcites [32] Duntas, 2002, Thyroid disease and lipids, Thyroid source

In the paper

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

In the paper

“patients with hypothyroidism (both overt and subclinical) exhibit impaired endothelial function, which improves with TH replacement therapy (14-16).”

What the sources say

• Not checked yetcites [14] Papaioannou, 2004, Treating hypothyroidism improves endothelial function, Metabolism source
• Not checked yetcites [15] Taddei, 2003, Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy, J Clin Endocrinol Metab source
• Not checked yetcites [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

In the paper

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

In the paper

“Hypothyroidism is associated with increased oxidation of LDL, which promotes atherogenesis and reverses with treatment (33,34).”

What the sources say

• Not checked yetcites [33] Diekman, 1998, Increased oxidizability of low-density lipoproteins in hypothyroidism, J Clin Endocrinol Metab source
• Not checked yetcites [34] Costantini, 1998, Effect of thyroid function on LDL oxidation, Arterioscler Thromb Vasc Biol source

In the paper

“Endothelial-dependent vasodilation is lower in overtly hypothyroid and SCH patients (51), and improves with levothyroxine treatment (15,16)”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [15] Taddei, 2003, Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy, J Clin Endocrinol Metab source
• Not checked yetcites [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

In the paper

“Overt and SCH are associated with diastolic hypertension, impaired vascular function, and increased carotid intima hyperplasia (45,47).”

What the sources say

• Not checked yetcites [45] Volzke, 2009, Subclinical hyperthyroidism and blood pressure in a population-based prospective cohort study, Eur J Endocrinol source
• Not checked yetcites [47] Cai, 2011, Blood pressure levels in patients with subclinical thyroid dysfunction: a meta-analysis of cross-sectional data, Hypertens Res source

In the paper

“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.”

In the paper

“Clinical features of this condition are pleural effusion, hepatic congestion, and fluid retention, which can improve with diuretic agents and beta-blockers (75).”

What the sources say

• Not checked yetcites [75] Biondi, 2012, Mechanisms in endocrinology: heart failure and thyroid dysfunction, Eur J Endocrinol source

In the paper

“Overt hyperthyroidism has been associated with 16% increased risk of major CV events, mainly due to higher incidence of HF events (74).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [98] Molinaro, 2012, Persistence of mortality risk in patients with acute cardiac diseases and mild thyroid dysfunction, Am J Med Sci source

In the paper

“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).”

What the sources say

• Not checked yetcites [31] Canaris, 2000, The Colorado thyroid disease prevalence study, Arch Intern Med source
• Not checked yetcites [37] Tunbridge, 1977, Lipid profiles and cardiovascular disease in the Whickham area with particular reference to thyroid failure, Clin Endocrinol (Oxf) source

In the paper

“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).”

What the sources say

• Not checked yetcites [85] Collet, 2012, Subclinical hyperthyroidism and the risk of coronary heart disease and mortality, Arch Intern Med source

In the paper

“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).”

What the sources say

• Not checked yetcites [60] Homoncik, 2007, Altered platelet plug formation in hyperthyroidism and hypothyroidism, J Clin Endocrinol Metab source

In the paper

“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).”

What the sources say

• Not checked yetcites [67] Cantürk, 2003, Hemostatic system as a risk factor for cardiovascular disease in women with subclinical hypothyroidism, Thyroid source

In the paper

“In summary, both TH deficiency and excess can alter the coagulation pathway, although the precise clinical relevance of this finding is unclear (Table 2).”

What the sources say

• Not checked yetcites (Table 2)

In the paper

“TH is a regulator of the tumor suppressor p53, which is activated during AMI, enhancing the mitochondrial apoptosis pathway (21).”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [114] Friberg, 2002, Rapid down-regulation of thyroid hormones in acute myocardial infarction: is it cardioprotective in patients with angina?, Arch Intern Med source

In the paper

“It is an iodinated derivative of benzofuran and is structurally similar to TH”

In the paper

“each molecule of the drug containing 2 iodine atoms, whereas T 4 has 4 and T 3 has 3 iodine atoms”

In the paper

“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.”

What the sources say

• Not checked yetcites [128] De Groot, 1999, Dangerous dogmas in medicine: the nonthyroidal illness syndrome, J Clin Endocrinol Metab source

In the paper

“SCH and SHyper, in contrast, occur in 6% and 3% of HF patients, respectively (129).”

What the sources say

• Not checked yetcites [129] Galli, 2010, The role of thyroid hormone in the pathophysiology of heart failure: clinical evidence, Heart Fail Rev source

In the paper

“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).”

What the sources say

• Not checked yetcites [117] Passino, 2009, Prognostic value of combined measurement of brain natriuretic peptide and triiodothyronine in heart failure, J Card Fail source

In the paper

“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.”

In the paper

“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.”

In the paper

“Clinical trials of TH therapy in AMI patients are underway”

What the sources say

• Not checked yetcites [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 yetcites [143] Mourouzis, 2011, Thyroid hormone and cardiac disease: from basic concepts to clinical application, J Thyroid Res

In the paper

“This favors p53 accumulation, and therefore enhances mitochondrial dysfunction and bcl-2-like protein 4 activation, resulting in extended myocardial cell loss (22).”

What the sources say

• Not checked yetcites [22] Li, 2010, miR-30 regulates mitochondrial fission through targeting p53 and the dynamin-related protein-1 pathway, PLoS Genet source

In the paper

“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).”

What the sources say

• Not checked yetcites [102] Razvi, 2012, Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality, Arch Intern Med source

In the paper

“As low levels of TH are associated with a decreased metabolic rate”

In the paper

“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.”

In the paper

“NTI occurs in 15% to 20% of patients with AMI (112,113).”

What the sources say

• Not checked yetcites [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 yetcites [113] Li, 2011, Negative association between free triiodothyronine level and international normalized ratio in euthyroid subjects with acute myocardial infarction, Acta Pharmacol Sin source

In the paper

“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).”

What the sources say

• Not checked yetcites [24] Matsumoto, 2013, Circulating p53-responsive microRNAs are predictive indicators of heart failure after acute myocardial infarction, Circ Res source

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [26] Pantos, 2007, Enhanced tolerance of the rat myocardium to ischemia and reperfusion injury early after acute myocardial infarction, Basic Res Cardiol source

In the paper

“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)”

What the sources say

• Not checked yetcites [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 yetcites [116] Wassen, 2002, Induction of thyroid hormone-degrading deiodinase in cardiac hypertrophy and failure, Endocrinology source

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [92] Owen, 2007, Thyroid disease and vascular function, Thyroid source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [72] Palmieri, 2004, Myocardial contractility and total arterial stiffness in patients with overt hyperthyroidism: acute effects of beta1-adrenergic blockade, Eur J Endocrinol source

In the paper

“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).”

What the sources say

• Not checked yetcites [31] Canaris, 2000, The Colorado thyroid disease prevalence study, Arch Intern Med source
• Not checked yetcites [37] Tunbridge, 1977, Lipid profiles and cardiovascular disease in the Whickham area with particular reference to thyroid failure, Clin Endocrinol (Oxf) source

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [127] Ertugrul, 2011, Prevalence of subclinical hypothyroidism among patients with acute myocardial infarction, ISRN Endocrinol source

In the paper

“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).”

What the sources say

• Not checked yetcites [116] Wassen, 2002, Induction of thyroid hormone-degrading deiodinase in cardiac hypertrophy and failure, Endocrinology source

In the paper

“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).”

What the sources say

• Not checked yetcites [65] Chadarevian, 2001, Components of the fibrinolytic system are differently altered in moderate and severe hypothyroidism, J Clin Endocrinol Metab source

In the paper

“Both hyper-and hypothyroidism can occur with amiodarone therapy.”

In the paper

“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.”

What the sources say

• Not checked yetcites [118] Pol, 2011, Left-ventricular remodeling after myocardial infarction is associated with a cardiomyocyte-specific hypothyroid condition, Endocrinology source

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“The degree of TH down-regulation is associated with higher impairment of cardiac function and higher inflammatory response (114,121).”

What the sources say

• Not checked yetcites [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 yetcites [121] Kimur, 2001, Correlation of circulating interleukin-10 with thyroid hormone in acute myocardial infarction, Res Commun Mol Pathol Pharmacol

In the paper

“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).”

What the sources say

• Not checked yetcites [118] Pol, 2011, Left-ventricular remodeling after myocardial infarction is associated with a cardiomyocyte-specific hypothyroid condition, Endocrinology source

In the paper

“Studies investigating coagulation in overt hypothyroidism have yielded conflicting results, with 2 studies showing hypercoagulability (62,63) and 1 study showing increased fibrinolysis (64).”

What the sources say

• Not checked yetcites [62] Squizzato, 2005, Thyroid diseases and cerebrovascular disease, Stroke source
• Not checked yetcites [63] Erem, 2003, Blood coagulation and fibrinolytic activity in hypothyroidism, Int J Clin Pract source
• Not checked yetcites [64] Gullu, 2005, Effects of levothyroxine treatment on biochemical and hemostasis parameters in patients with hypothyroidism, Eur J Endocrinol source