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Thyroid Hormones and Cardiovascular Function and Diseases

We appear to be headed in the direction of cardiologists understanding more about the impact of thyroid hormones than endocrinologists.

Unfortunately, the rest of this paper is behind a paywall.

Thyroid Hormones and Cardiovascular Function and Diseases

Salman Razvi, MDa, b, , , Avais Jabbar, MDa, c, Alessandro Pingitore, MDd, Sara Danzi, PhDe, Bernadette Biondi, MDf, Irwin Klein, MDg, Robin Peeters, MDh, Azfar Zaman, MDc, i, Giorgio Iervasi, MDd

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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.

21/04/2018 21:58 Edited to add:

The eagle-eyed among you might notice that the picture accompanying this post (taken from the actual paper) does NOT mentioned TRH. Which is the subject of another of my very recent posts:

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Thanks Helvella, cardiologists appear to be much more ahead of the game than endocrinologists, who seem to have closed their minds to possibilities and think they have it all licked.


One of my frequent posts - and bought the book ! All research papers from when Cardiologists and Endocrinologists came together in Italy for the purposes of research back in 2004 :-)


How 'readable' is this book, Marz? Brain fog is making it hard for me to concentrate. I'm tempted to buy it but am wondering if it will be another one I can't take in a word of if it's too complex....

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It is just Research Papers - so yes a hard read. I just read the introduction and the conclusion of most Research Papers :-)

If you Look Inside on-line - you can read the Contents pages and see what they contain. Liothyronine - T3 - seems to be the star of the show ! If I lived in the UK I would lend you my copy .... :-(


ah, thank you! I could just about stretch to the £35 for a used copy... but I seem to be collecting quite a stash of books I can't concentrate on...! I did take a peek at the look inside and it didn't seem tooooo unintelligble lol. Will have a thunk and consult my wallet!

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Most of the papers are on PubMed - so have a google. 😊


Thanks for the link. I winced at the price! Is there a digest of it anywhere on line that you know of? My systolic pressure is up the spout ☹️


They should all be on PubMed 😊


My Gastro Consultant is good on thyroid stuff 🙂


That's interesting! Lucky find (tho' sorry you need recourse)!

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My lipids consultant is rubbish, wouldn't acknowledge any link at all between low levels of T3 and heart disease. Bah! Good to hear some consultants are clued up though :)


Full Text:

Author(s): Avais Jabbar [1, 2]; Alessandro Pingitore [3]; Simon H. S. Pearce [1, 4]; Azfar Zaman [1, 2]; Giorgio Iervasi [3]; Salman Razvi (corresponding author) [1, 5]

Cardiovascular disease is a model of chronic degenerative disease, and at present is the leading cause of death worldwide, accounting for >15 million deaths each year [1]. According to 2020 WHO projections, cardiovascular diseases and their complications, in particular postischaemic heart failure (HF), will be the most important cause of morbidity and death worldwide, with high costs to health-care systems [2]. These forecasts reinforce the need to develop new therapeutic and preventive strategies to reduce cardiovascular disease morbidity and mortality [3].

Although standard risk factors and secondary prevention strategies for cardiovascular disease are well documented and firmly established, the role of other mediators in initiating and exacerbating underlying cardiovascular disease is increasingly acknowledged. The role of thyroid hormones -- particularly when abnormal -- in aggravating cardiovascular disease is recognized, given that thyroid hormone receptors are present in both myocardial and vascular endothelial tissues [4], thereby enabling changes in circulating thyroid hormone concentrations to modulate end-organ activity. However, the clinical significance of mild thyroid overactivity (subclinical hyperthyroidism) and underactivity (subclinical hypothyroidism) is uncertain. Moreover, the absence of high-quality clinical trials has led to controversy over the optimal protocols for diagnosing subclinical thyroid diseases and whether treatment of patients with mildly abnormal serum-thyroid results is appropriate. From a clinical perspective, 'subclinical' denotes the presence of disease without manifest symptoms and suggests the presence of either mild or early disease. Importantly, thyroid function tests are performed very frequently; for example, 25% of people in the UK have their thyroid function assessed annually [5]. Frequent testing can lead to detection of incidentally abnormal thyroid function parameters and, in the absence of high-quality evidence (either for or against treatment), can generate confusion as to the best evidence-based management of subclinical thyroid diseases.

Minor changes in circulating thyroid hormone concentrations can adversely affect the cardiovascular system, as evidenced by findings from observational studies showing that both subclinical hypothyroidism and subclinical hyperthyroidism are associated with a 20-80% increase in vascular morbidity and mortality [6, 7, 8, 9, 10]. These findings indicate that thyroid hormone status has great importance as a vascular risk factor in the general population, because [greater than equal ro]10% of women aged >55 years have subclinical hypothyroidism [6, 11] and 1-2% have subclinical hyperthyroidism [10, 12, 13]. Unfortunately, the role of subclinical thyroid disease as a cardiovascular risk factor is underrecognized, owing to the lack of high-quality outcome trial data to guide practice after the abnormal thyroid function is identified, and because of the lack of commercial exploitability.

This Review is intended for health-care professionals and researchers who are involved in caring for patients with cardiovascular disease or are studying potential treatments to ameliorate the complications of these conditions. The aim of this Review is to inform and update readers on the influence of thyroid hormones in the pathogenesis and the management of cardiovascular disease, and to summarize the current literature describing the effect of thyroid hormones in HF and acute myocardial infarction (MI).

Historical perspective

The association between thyroid dysfunction and cardiovascular disease is not new. In 1878, decades before thyroid function tests became available, William Greenfield described the autopsy findings of a middle-aged woman with myxoedema -- a severe form of hypothyroidism -- as having "much serous effusion in the pericardium ... the heart was large ... the arteries were everywhere thickened, the larger ones atheromatous" (REF 14). Soon after, clinical and autopsy accounts describing atherosclerosis in patients with myxoedema started to be reported [15, 16], and it became apparent that the clinical condition of myxoedema was linked to a poorly functioning thyroid gland. However, the diagnosis of myxoedema was based purely on clinical grounds and, in the absence of modern thyroid function assays, milder and less clinically apparent forms of the disease would have been missed. In 1891, George Murray subcutaneously injected sheep thyroid hormone extract into a patient with clinical features of myxoedema, producing dramatic improvement in symptoms and facial appearance [17]. Over the subsequent 30 years, Murray switched to oral thyroid extract collected from a pool of sheep, the glands being obtained from an abattoir.

Commercial production of a synthetic thyroid hormone (levothyroxine) took many years. This thyroxine was not available until 1949 and, even then, tablets of desiccated thyroid extract were the mainstay of replacement for many years [18]. Clinical trials in patients with myxoedema showed that this new therapeutic agent had positive effects in reducing high cholesterol levels [19] and reducing cardiovascular morbidity [20] and mortality [21]. From 1965 onwards, the first generation of radioimmunoassays to estimate serum thyroid-stimulating hormone (TSH; also known as thyrotropin) were developed, although these assays had limited functional sensitivity [22]). In 1967, in a case-control study including 25 autopsies from inadequately-treated patients with hypothyroidism and 50 age-matched and sex-matched control autopsies, Belgian researchers reported that the presence and severity of coronary artery disease was more common in patients with hypothyroidism (96%) than in euthyroid individuals (60%), and that left ventricular hypertrophy and dilatation was more frequent in the group with hypothyroidism [23, 24]. In 1977, Tunbridge et al . performed the first cross-sectional, cohort study in Whickham, UK, and concluded that no association existed between subclinical hypothyroidism and presence of cardiovascular disease, although a weak relationship was seen in women with subclinical hypothyroidism and minor electrocardiogram changes [25].

These initial data suggesting a possible link between mild or inadequately treated hypothyroidism and cardiovascular disease, as well as the benefits of levothyroxine in reducing cholesterol and cardiac morbidity and mortality, led investigators to consider the use of thyroid hormone analogues in euthyroid individuals at high risk of cardiovascular disease, with the aim of reducing the deleterious effects of thyroxine excess seen with levothyroxine therapy, while preserving its recognized beneficial effects on cardiovascular risk factors [26, 27]. The negative results of a trial of dextrothyroxine -- a low-activity dextro-isomer of thyroxine -- in male survivors of acute MI [28] curbed the enthusiasm for using thyroid hormone therapy in patients with cardiovascular disease. This trial showed increased arrhythmias and higher mortality in the treated group compared with untreated patients, probably owing to contamination with levothyroxine [28] and the supraphysiological doses of dextrothyroxine used in the trial (more than twice the normal endogenous thyroxine production) [29]. Another trial on the thyroid hormone analogue diiodothyropropionic acid in patients with HF showed higher heart rate and symptoms suggestive of hyperthyroidism in the treated patients [27, 30]. Of note, thyroid hormone analogues were used in both studies rather than native thyroid hormones. The results of these early trials prejudiced clinicians and curbed enthusiasm of researchers and pharmaceutical companies in developing and researching the use of thyroid hormones and its analogues at therapeutic doses in patients with cardiovascular disease. In the past decade, studies on the use of the liver-selective, thyroid hormone receptor agonist eprotirome in patients with resistant and familial hypercholesterolaemia showed a beneficial effect on blood lipid parameters [31], but this therapy has not progressed to large-scale, phase III studies owing to concerns over potential liver and cartilage injury [32].

Thyroid hormone action on the heart

The thyroid gland secretes two main iodinated hormones, T3 (3,5,3'-triiodothyronine) and T4 (3,5,3',5'- tetraiodothyronine; also known as thyroxine). Both molecules can generate biological activity in responsive tissues by binding to the thyroid hormone receptors; however, T3 is considered the biologically active hormone. The affinity of the thyroid hormone receptors is approximately tenfold higher for T3 than for T4 (Ref. 33); therefore, T4 must be converted to T3 to produce potent thyroid hormone receptor-mediated effects. Although T 4 is a prohormone for T3 , T4 can act directly through thyroid hormone receptors in a variety of tissues, such as blood vessels. For example, T4 can interact with the plasma membrane integrin [alpha]v [beta]3 , indicating that T4 is directly proangiogenic [34].

The thyroid gland secretes <20% of circulating T3 , with the bulk of T3 being produced from T4 in extrathyroidal tissues by a process of deiodination of a single iodine atom ([Box 1]). The most relevant pathway of thyroid hormone metabolism is regulated by three selenocysteine enzymes called deiodinases [35]. Two deiodinase enzymes -- type I iodothyronine deiodinase (DIO1) and type II iodothyronine deiodinase (DIO2) -- lead to extrathyroidal T3 production. DIO1 is active mostly in the liver and the kidney, and produces 15-20% of total circulating T3 (Ref. 35). DIO2 activity is located in brown adipose tissue, pituitary gland, brain, and heart, and is responsible for the majority (two-thirds) of T3 production [36, 37]. The third deiodinase, thyroxine 5-deiodinase (DIO3), catabolizes both T3 and T4 to inactive products, leading to the termination of thyroid-hormone action. Thyroid hormone status of an organism is dependent on both serum thyroid hormone levels and intracellular tissue levels, which are regulated by deiodinases. For example, increased DIO3 activity in cardiomyocytes decreases the levels of T3 in left ventricular tissue, causing a local hypothyroid state [38].

Thyroid hormones have a broad range of effects on the cardiovascular system, particularly on the heart (Fig. 1). Thyroid hormones influence cardiac status in three ways: by direct genomic actions on cardiomyocytes through binding to nuclear receptors, which leads to the regulation of the expression of target genes; by extranuclear, nongenomic actions on the ion channels in the cardiomyocyte cell membrane; and through the effects of T3 and T4 on the peripheral circulation, which determines cardiovascular haemodynamics, cardiac filling, and systolic contractility [4, 39].

In the cardiomyocyte, T3 binds to thyroid hormone receptors in the nucleus, which in turn bind to thyroid hormone response elements in the regulatory regions of target genes to regulate transcription. The two main thyroid receptors are thyroid hormone receptor-[alpha], which is highly expressed in cardiomyocytes [40], and thyroid hormone receptor-[beta]. Thyroid hormone receptors are unique in that they can bind to thyroid hormone response elements in the absence of thyroid hormones, leading to repression of transcription of target genes [41]. Therefore, the regulation of essential genes in the cardiomyocyte is dependent on the availability of thyroid hormones [42].

Thyroid hormone activity in the cardiomyocyte regulates myocardial contractility and systolic function. Thyroid hormones activate the expression of genes encoding sodium/potassium-transporting ATPases, myosin heavy chain-[alpha] (myosin 6; encoded by MYH6 ), and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2; encoded by ATP2A2 ), and negatively regulate the transcription of myosin heavy chain-[beta] (myosin 7; encoded by MYH7 ) and phospholamban (PLN ) [43, 44, 45] (Fig. 1). The two myosin heavy chains are important components of the contractile apparatus of the cardiomyocyte [46]. SERCA2 and its inhibitor PLN regulate the reuptake and release of calcium from the sarcoplasmic reticulum, thereby regulating the amount of calcium available for systolic contraction, which can determine diastolic relaxation of the heart. Thyroid hormones, by inducing increased levels of SERCA2 and decreased levels of PLN in the sarcoplasmic reticulum, promote the reuptake of calcium during diastole, leading to improved ventricular relaxation [47, 48, 49, 50]. Thyroid hormones also have a direct inotropic effect on the heart by positively regulating the gene expression of the [beta]1 -adrenergic receptor [51].

In addition, thyroid hormones influence cardiac chronotropy through both genomic and nongenomic effects on components of the adrenergic-receptor complex and on sodium, potassium, and calcium channels [4]. The effect of thyroid hormones on cardiac chronotropy manifests as tachycardia and increased risk of atrial fibrillation (AF) in hyperthyroid states, and as bradycardia and reduced cardiac contractility in hypothyroidism [4].

Nongenomic effects of thyroid hormones on cardiomyocytes and the systemic vasculature include activation of sodium, potassium, and calcium membrane ion channels [4], effects on the mitochondrial membrane and mitochondriogenesis [41], and involvement in signalling pathways of cardiomyocytes and vascular smooth muscle cells [48]. Thyroid hormones activate phosphatidylinositol 3-kinase (PI3K) / serine/threonine-protein kinase (AKT) signalling pathways, inducing production of endothelial nitric oxide and a subsequent reduction in the systemic vascular resistance [52]. Thyroid hormones influence cardiac mitochondrial function [53], and changes in the circulating levels of thyroid hormones might lead to impaired myocardial bioenergetic status and function [54]. Other nongenomic actions of thyroid hormones include vasodilatation [55]. Thyroid hormones decrease systemic vascular resistance by increasing production of nitric oxide and by increasing calcium reuptake within the arterioles, which leads to smooth muscle relaxation [55]. This decrease in systemic vascular resistance is also a result of the direct repression of PLN expression and the increase in tissue metabolism and thermogenesis induced by thyroid hormones [56]. The decrease in systemic vascular resistance induced by thyroid hormones, together with their direct inotropic effects, lead to an increase in cardiac output, as has been shown in patients with hyperthyroidism [57] and also after T3 infusion in high-risk patients undergoing CABG surgery [58].

The renin-angiotensin-aldosterone system also has an important role in the haemodynamic effects of thyroid hormones. The initial decrease in systemic vascular resistance induced by thyroid hormones leads to decreased perfusion in the kidneys, which increases renin and aldosterone levels [59]. The activation of the renin-angiotensin-aldosterone axis leads to an increase in the plasma volume and, therefore, an increase in cardiac preload, which is another explanation for the increase in cardiac output induced by thyroid hormones [4].

Overt and subclinical hyperthyroidism

Overt hyperthyroidism is commonly caused by stimulation of the TSH receptor by autoantibodies (Graves disease) or as a result of autonomous production of thyroid hormones by thyroid nodules [39] ([Box 2]; Table 1). The prevalence of overt hyperthyroidism in the general population is 0.5% [39].

Tachycardia is a common sign of overt hyperthyroidism, and 5-15% of patients with overt hyperthyroidism present with AF [4]. Normalization of thyroid hormone levels leads to the reversion to normal sinus rhythm in approximately 60% of patients who have AF owing to hyperthyroidism [60]. Shortness of breath during minimal exertion is also commonly reported by patients with hyperthyroidism [61]; however, the aetiology of this symptom has not been clearly defined. Moreover, hyperdynamic circulation -- characterised by increased preload and contractility, reduced systemic vascular resistance, and high heart rate, leading to a 50-300% increase in cardiac output -- is common in overt hyperthyroidism [39]. If overt hyperthyroidism is left untreated, or in those individuals with severe longstanding hyperthyroidism, this increased cardiac output can lead to symptoms and signs of HF as a result of left ventricular hypertrophy, arrhythmias (such as AF), and an increase in cardiac preload secondary to fluid overload [61]. Observational studies show that patients who have had an episode of hyperthyroidism have high long-term cardiovascular mortality, unless they received radioiodine therapy to induce overt hypothyroidism [62].

Hyperthyroidism also has a role in the pathogenesis of pulmonary hypertension [63, 64]. Epidemiological evidence supports a strong relationship between hyperthyroidism, pulmonary arterial hypertension, and right ventricular HF, with two studies showing a 43% and 44% prevalence of pulmonary arterial hypertension in patients with hyperthyroidism [63, 64]. Whether this relationship is incidental or thyroid hormones directly induce such a state is unclear. One potential mechanism is left ventricular HF and a hyperdynamic circulation secondary to an excess of thyroid hormones, which leads to an increase in pulmonary arterial pressure [61]. Studies in animal models have also shown that thyroid hormones cause endothelial cell proliferation and angiogenesis in pulmonary hypertension by binding to integrin [alpha] v [beta]3 and fibroblast growth factor receptors [65, 66]. These changes reversed after thyroidectomy [65, 66]. Few clinical studies exist on the effects of treatment of hyperthyroidism on pulmonary hypertension. The largest study included 64 patients with newly diagnosed Graves disease, of whom 28 had pulmonary arterial hypertension [64]. Follow-up echocardiography after treatment of hyperthyroidism in these patients showed normalization of pulmonary pressures in all patients except one [64].

Subclinical hyperthyroidism is defined by low circulating TSH levels with serum concentrations of T3 and T4 within the reference range [67, 68, 69, 70] ([Box 2]). Subclinical hyperthyroidism can be caused by exogenous (for example, secondary to excessive thyroid hormone replacement therapy or use of other drugs such as high-dose glucocorticoids) or endogenous (such as an underlying thyroid disease causing thyroid overactivity) factors. A substantial proportion (15-20%) of patients prescribed levothyroxine have a low TSH level, indicating exogenous subclinical hyperthyroidism [11, 71, 72, 73]. By contrast, the prevalence in the general population of endogenous subclinical hyperthyroidism depends on age, sex, and iodine intake, with a reported prevalence of 0.6-1.8% in iodine-sufficient areas in Iceland and the USA, and as high as 9.8% in iodine-deficient areas in Denmark [10, 12, 74]. Whether exogenous and endogenous subclinical hyperthyroidism are equivalent in terms of cardiovascular effects or the risk of cardiovascular disease is currently unclear.

Small, case-control studies including predominantly young patients (aged <60 years) with subclinical hyperthyroidism showed a higher heart rate, increased frequency of atrial and ventricular premature beats, and greater left ventricular mass compared with euthyroid individuals [75, 76]. However, this finding was not confirmed in larger, population-cohort studies in older individuals (aged >50-70 years) [77, 78]. Carotid intima-media thickness was also shown to be higher in patients with subclinical hyperthyroidism than in euthyroid individuals and patients with hypothyroidism [79]. A population-based study showed that low serum TSH is an independent risk factor for increased plasma levels of fibrinogen, which in turn have been associated with an elevated risk of cardiovascular events [80]. These risk factors would be expected to lead to an elevated risk of cardiovascular disease in patients with subclinical hyperthyroidism and, in keeping with this hypothesis, several observational studies showed an association between endogenous subclinical hyperthyroidism and incident cardiovascular disease [9, 81], AF [10, 82, 83, 84, 85], and cardiac dysfunction [75, 86]. A patient-level meta-analysis of 10 prospective, cohort studies including a total of 52,674 participants confirmed a strong association between subclinical hyperthyroidism and adverse cardiovascular outcomes [85]. After adjustment for age and sex, subclinical hyperthyroidism was significantly associated with increased coronary heart disease mortality (HR 1.29, 95% CI 1.02-1.62), and with increased risk of coronary heart disease events (HR 1.21, 95% CI 0.99-1.46) and incident AF (HR 1.68, 95% CI 1.16-2.43) [85] compared with euthyroid states. These data suggest a substantial contribution of mild thyroid hormone excess to the risk of developing AF, with an attributable risk (the number of cases of a disease among exposed individuals that can be attributed to that exposure) of 6.2% in the general population and up to 41.5% in those individuals with subclinical hyperthyroidism [85]. Interestingly, several studies also showed a positive correlation between serum T4 levels -- even within the reference range -- and risk of AF [84, 87, 88, 89]. Furthermore, even in patients with exogenous subclinical hyperthyroidism owing to levothyroxine use, those with fully suppressed serum TSH levels have an excess of cardiovascular and dysrhythmia events [90].

A definitive conclusion on the relationship between subclinical hyperthyroidism and cardiac outcomes is hampered by the varied and inconsistent methodologies used in the observational studies. Population heterogeneity, the different TSH cut-off levels used to define subclinical hyperthyroidism, the covariates included in the analyses, and different cardiovascular disease definitions all serve to invalidate interstudy comparisons. In addition, interpretation of a low serum TSH is clouded because this biochemical finding is associated with many chronic inflammatory disorders -- similar to the sick euthyroid syndrome, where TSH levels are usually slightly low, often in conjunction with a low or low-normal serum levels of free T3 -- and is also highly prevalent in healthy individuals at old age (>70-75 years) [91]. Most importantly, in the absence of randomized, controlled trials to examine the effects of treating subclinical hyperthyroidism on clinically relevant outcomes, the published consensus statement [68] and management guidelines [69, 70, 92] must be interpreted as expert opinion and in the context of other health issues present in each patient. Nevertheless, treatment of subclinical hyperthyroidism is advocated in international guidelines to prevent long-term complications, particularly when serum TSH levels remain persistently fully suppressed (<0.10 mU/l) in the absence of other explanations (such as use of levothyroxine or opiates). The European Thyroid Association guidelines [92] advocate treatment in patients aged >65 years with TSH levels <0.10 mU/l to ameliorate the risk of cardiovascular events, fractures, or progression to overt hyperthyroidism. Treatment can also be considered in patients aged >65 years with mildly low TSH levels (0.10-0.39 mU/l), particularly if they have underlying cardiovascular disease or other comorbidities [92]. In patients aged <65 years with TSH levels <0.10 mU/l, treatment is indicated in those patients with cardiovascular risk factors or comorbidities, persistent thyroid disease, and/or symptoms of thyroid disease, especially if thyroid autoantibodies are present [92]. In practice, further evidence of a tendency to thyroid hormone excess, either through demonstration of actual thyroid disease (by antibody assays or thyroid imaging) or a serum free T3 at the higher end of the reference range (6-7 pmol/l), gives a more robust support to endorse treatment of subclinical hyperthyroidism.

Overt and subclinical hypothyroidism

Overt hypothyroidism is diagnosed when serum TSH is elevated (usually >10 mU/l) and circulating free T4 is low (<9-10 pmol/l) ([Box 3]). The prevalence of overt hypothyroidism in nonpregnant adults is 0.2-2.0% [11, 93]. The causes of hypothyroidism are outlined in Table 1.

Overt hypothyroidism has several cardiac manifestations, including a reduction in cardiac output and cardiac contractility, a decrease in heart rate, and an increase in peripheral vascular resistance [94]. Marked changes in modifiable atherosclerotic risk factors also accompany overt hypothyroidism, including hypercholesterolaemia, diastolic hypertension, increased carotid intima-media thickness, and reduced production of endothelial-derived relaxation factor (nitric oxide) [95]. All these clinical features are reversible with thyroid hormone replacement therapy [95].

Subclinical hypothyroidism is diagnosed when serum thyroid hormones are within the reference range, but serum TSH concentrations are elevated ([Box 3]). Subclinical hypothyroidism can be mild (TSH >4.0-4.5 mU/l, but <10.0 mU/l) or severe (TSH >10.0 mU/l). However, no consensus exists on the 'normal' upper range of serum TSH, leading to controversy on both the definition and the clinical significance of subclinical hypothyroidism [96]. Prevalence of subclinical hypothyroidism in the general, adult population is 4-20% [69]. This wide prevalence range is a result of differences in age, sex, body mass index, race, dietary iodine intake, and the cut-off concentrations of serum TSH that are used to define the condition. Prevalence of raised serum TSH concentrations is higher in white than in black populations [97]. Estimations indicate that at least 10% of old women (aged >60 years) have subclinical hypothyroidism [98]; this prevalence has potential relevance as a vascular risk factor in the wider population.

The most frequent cardiac abnormality in individuals with subclinical hypothyroidism is diastolic dysfunction owing to impaired ventricular filling and relaxation [99, 100]. Although studies investigating systolic dysfunction in individuals with subclinical hypothyroidism have yielded inconsistent results, a robust study demonstrated that subclinical hypothyroidism was associated with systolic dysfunction (assessed by cardiac MRI) that reversed with thyroxine replacement therapy [101]. The presence of subclinical hypothyroidism has also been associated with diastolic and systolic dysfunction during exercise, resulting in impaired exercise tolerance in these individuals [102, 103]. Subclinical hypothyroidism can impair relaxation of vascular smooth muscle cells [39], inducing increases in systemic vascular resistance and arterial stiffness, and can also induce changes in endothelial function by reducing nitric oxide availability, without apparent clinical implications [104]. These findings are supported by population studies, with the Whickham Survey cohort [8] revealing higher systolic and diastolic blood pressures and total cholesterol concentrations in individuals with subclinical hypothyroidism than in euthyroid individuals, and the EPIC-Norfolk study [105] showing that, despite a worse profile of risk of cardiovascular disease in patients with subclinical hypothyroidism, coronary heart disease and all-cause mortality did not increase in the 10.6 years of follow-up.

Evidence from population studies on the association between subclinical hypothyroidism and cardiovascular morbidity and mortality is conflicting. Some prospective, population-based, cohort studies showed an increased risk of cardiovascular disease and death in individuals with subclinical hypothyroidism [7, 8, 106], but these findings were not confirmed in other studies [105, 107]. Patient-level meta-analysis of several prospective, cohort studies (with a total of 542,494 person-years of follow-up) showed that subclinical hypothyroidism is associated with a higher risk of cardiovascular events and death in people with high serum TSH levels, particularly in those with TSH levels >10 mU/l (Ref. 108).

Evidence from observational studies suggests a link between subclinical hypothyroidism and adverse cardiovascular outcomes [109, 110]. However, no randomized clinical trials are available to show whether improvements in cardiovascular events occur with thyroid hormone treatment of subclinical hypothyroidism. Small, interventional trials of levothyroxine therapy in individuals with subclinical hypothyroidism reported improvements in left ventricular function, vascular endothelial function, and atherogenic lipid particles, as shown by surrogate markers [39, 69]. Several other studies in patients with subclinical hypothyroidism showed similar results of improved cardiac function with levothyroxine therapy [99, 100, 101]. In an observational study including 3,093 patients with raised serum TSH, patients aged <70 years who were treated with levothyroxine had fewer cardiovascular events than untreated patients [111]. However, in individuals aged >70 years (n = 1,642), levothyroxine treatment had no benefit [111]. Interestingly, a small, interventional trial in patients with subclinical hypothyroidism showed improvement in cardiac mitochondrial function with levothyroxine treatment [54]. This study provides a novel insight at the subcellular level of the action of thyroid hormones in cardiac tissue [54] (Fig. 2).

Owing to the lack of evidence from prospective, randomized, controlled trials in subclinical hypothyroidism, international guidelines indicate that treatment should be considered only in those individuals with severe disease (serum TSH >10 mU/l), with symptoms of hypothyroidism, or in individuals aged <70 years, particularly if they also have other cardiovascular risk factors [112].

Cardiovascular risk factors

Hyperlipidaemia. Thyroid hormones are involved in lipid metabolism [95]. Overt and subclinical hyperthyroidism do not adversely influence lipid parameters [113] (Table 2). By contrast, the association between overt hypothyroidism and hyperlipidaemia has been known for many years, with some estimates showing a link in up to 90% of patients with overt hypothyroidism [94, 114]. Elevated plasma lipid levels are also evident in some patients with subclinical hypothyroidism [115], suggesting an increased risk of atherosclerosis in these individuals. However, population-based studies have shown conflicting findings. In some studies, such as the Whickham [93] and NHANES III [116] surveys, no link was found between subclinical hypothyroidism and hyperlipidaemia. By contrast, other studies showed a positive association between increasing serum lipid concentrations and serum TSH levels [116, 117].

The causes of hyperlipidaemia in an underactive thyroid state are the decreased expression of hepatic LDL receptors [114] -- which reduces cholesterol clearance from the bloodstream -- and the reduced activity of cholesterol-[alpha]-monooxygenase [114, 118], an enzyme that breaks down cholesterol. Randomized, placebo-controlled trials designed to assess whether levothyroxine treatment in individuals with subclinical hypothyroidism has a beneficial effect on LDL and total cholesterol levels had heterogeneous results. Some of these trials have shown a beneficial effect of levothyroxine replacement therapy on lipid profiles [119, 120, 121], whereas other studies have not [122, 123]. Such differences are probably the result of different population groups, varying severity of hypothyroidism, the presence of thyroid antibodies, different doses of levothyroxine, and the age of the participants. Meta-analyses of clinical trials indicate that levothyroxine therapy leads to a modest reduction in serum total cholesterol levels (approximately 0.2 mmol/l) in suboptimally treated patients with hypothyroidism or subclinical hypothyroidism [124]. A Cochrane review including six randomized clinical trials that had an assessment of lipid parameters showed that levothyroxine treatment for subclinical hypothyroidism had no overall effects in reducing plasma levels of total cholesterol, HDL, or LDL [125]; although a subgroup analysis showed a trend towards reducing LDL levels in patients with serum LDL >155 mg/dl (Ref. 125). In two randomized clinical trials that were published after the Cochrane meta-analysis, the reduction of plasma LDL cholesterol with levothyroxine was approximately 0.3 mmol/l (11.6 mg/dl) [119, 126].

Blood pressure and vascular function. The net effect of overt hyperthyroidism on blood pressure is variable depending on the increase in cardiac output versus the reduction in systemic vascular resistance, as evidenced by the observation that some patients with hyperthyroidism develop systolic hypertension [127, 128]. The relationship between subclinical hyperthyroidism and hypertension is less clear. Most observational studies (including a meta-analysis) suggest subclinical hyperthyroidism is not linked to hypertension [129, 130, 131]; however, some studies have shown a positive association [132, 133]. Furthermore, in one study restoration of euthyroidism after treatment of overt hyperthyroidism led to a reduction in systolic blood pressure [133].

Overt and subclinical hypothyroidism are associated with diastolic hypertension and impaired vascular function [4] (Table 2). The cause of hypertension in these patients is an increase in systemic vascular resistance, endothelial dysfunction, increased arterial stiffness, and low renin levels, most probably owing to the lack of the normal vasodilatory effects of T3 (Refs 69,127). Some studies have shown an isolated elevation in diastolic blood pressure in hypothyroidism [134, 135], whereas one study found both the systolic and diastolic blood pressure to be elevated [136].

Central arterial stiffening increases cardiac afterload and is an important predictor of all-cause mortality, as well as being a precursor for atherosclerosis [137, 138]. Pulse-wave velocity -- a measure of arterial stiffness -- increases in hypothyroid states and levothyroxine therapy has been shown to improve this parameter [139, 140]. Arterial stiffness also has been shown to increase in patients with subclinical hypothyroidism with or without autoimmune thyroiditis, which decreased after levothyroxine therapy [141, 142, 143].

Endothelial dysfunction is involved in the early steps of atherosclerosis development, and is associated with an increased risk of cardiovascular events [144]. Endothelial-dependent vasodilatation is lower in patients with overt hypothyroidism or with subclinical hypothyroidism [145]. This finding is further supported by randomized, controlled trials showing that levothyroxine treatment improves endothelial function in patients with subclinical hypothyroidism [119, 146].

Numerous factors could potentially contribute to arterial stiffness and endothelial dysfunction in subclinical hypothyroidism and overt hypothyroidism. Hyperlipidaemia is probably one cause because of its role in atherosclerosis [137, 146]. Thyroid autoantibodies might also have a role in endothelial dysfunction, with evidence showing that, in patients with subclinical hypothyroidism owing to thyroid autoimmunity, the endothelial dysfunction was only partially reversed after levothyroxine therapy [146]. Low-grade chronic inflammation resulting from the autoimmune process might underlie the endothelial dysfunction in most patients with subclinical hypothyroidism [147, 148, 149, 150]. The observation that vascular adhesion molecules such as E-selectin and P-selectin are increased in the thyroid tissue of patients with Hashimoto thyroiditis [151] -- an autoimmune thyroid disease -- indicates that thyroid antibodies might have a crucial role in inflammatory processes. Both hyperlipidaemia and thyroid antibodies are thought to reduce the expression of endothelial nitric oxide synthase and, therefore, impair the capacity of the artery to vasodilate [146]. In the Rotterdam study [6], a cross-sectional analysis including 1,149 women, the prevalence of aortic calcification and MI was higher in women with subclinical hypothyroidism than in euthyroid women, and this association was even stronger in patients with subclinical hypothyroidism and thyroid antibodies.

Finally, thyroid hormones have important effects on the endothelial cell through the thyroid hormone receptor-[alpha]1 and thyroid hormone receptor-[beta]. Activation of thyroid hormone receptor-[alpha]1 increases coronary blood flow and decreases coronary resistance in mouse models, improving cardiac contractility in ischaemia-reperfusion injury [152]. Another important effect of the activation of thyroid hormone receptor-[alpha]1 is vascular myocyte relaxation mediated by increased production of nitric oxide in endothelial and vascular smooth muscle cells through the activation of PI3K/AKT signalling and nitric oxide synthase [153]. Activation of thyroid hormone receptor-[beta] by thyroid hormones induces angiogenesis through the activation of the mitogen-activated protein kinase (MAPK) pathway [66]. MAPK pathway activation leads to the transcription of several proangiogenic genes, such as vascular endothelial growth factor (VEGF ) [154], basic fibroblast growth factor (FGF2 ) [154, 155] and angiopoietin (ANGPT ) [154].

Thrombosis. Overt and subclinical hyperthyroidism have been associated with alterations in the coagulation pathway [80, 156] (Table 2). However, whether these biochemical abnormalities have any clinical consequences remains unclear. The reported increase in cerebrovascular events owing to cerebral thrombosis in overt hyperthyroidism warrants further scrutiny [157], particularly to investigate if the reported risk of cerebrovascular events is caused by increased blood thrombogenicity or by alterations in the vascular tree (for example, an increase in the carotid intima-media thickness or the vascular plaques that are observed in subclinical hyperthyroidism) [158].

Alterations in coagulation parameters in subclinical hypothyroidism might have a role in the development of atherosclerosis. In a study comparing women with subclinical hypothyroidism with euthyroid women, factor VII activity and the ratio of factor VII activity to factor VII antigen were significantly increased in women with subclinical hypothyroidism, whereas no differences were found in von Willebrand factor or in any of the other haemostatic factors tested [159]. In another study, decreased antithrombin III activity and increased levels of fibrinogen, factor VII, and plasminogen activator inhibitor antigen were found in patients with subclinical hypothyroidism compared with euthyroid individuals [160], which might explain a hypercoagulable state in these patients. A study in which blood thrombogenicity was assessed with the Badimon perfusion chamber -- a model that simulates coronary artery blood flow through an ex vivo artery strip -- showed that patients with subclinical hypothyroidism 7-10 days after non-ST-segment elevation MI had a higher thrombus burden than euthyroid patients despite the use of appropriate secondary preventive agents, including aspirin and clopidogrel [161]. This finding might also explain the high risk of cardiovascular disease seen in patients with subclinical hypothyroidism, as the hypothyroid state is probably thrombogenic.

By contrast, studies analysing blood coagulation in patients with overt hypothyroidism have conflicting results. Some studies have shown hypercoagulability in patients with overt hypothyroidism [162, 163], whereas other studies have shown increased fibrinolysis [164, 165, 166]. A study including 20 patients with overt hypothyroidism showed that these patients had a hypofibrinolytic state, with increased levels of fibrinogen and plasminogen activator inhibitor [163]. Conversely, other studies showed increased fibrinolysis in patients with overt hypothyroidism, demonstrating that these patients had reduced von Willebrand factor activity -- which affects primary haemostasis -- and increased bleeding times compared with euthyroid individuals [164, 165, 166]. Interestingly, a study comparing euthyroid controls with patients with either moderate or severe hypothyroidism showed that 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 [167].

Heart failure

HF is a complex clinical condition that results from impaired efficiency of the heart as a pump. The most common cause of HF in the Western world is coronary artery disease, and many patients have a history of MI [1]. The myocardium is very sensitive to circulating thyroid hormone levels and alterations in the status of thyroid hormones can lead to HF, and HF itself can alter thyroid hormone status.

Overt hypothyroidism can cause left ventricular diastolic dysfunction as a result of the downregulation of the gene encoding SERCA2 (Ref. 4). A decrease in SERCA2 protein levels will subsequently lead to reduced reuptake of calcium during diastole and, therefore, impaired ventricular relaxation in these patients [168, 169]. This altered ventricular relaxation impairs left ventricular filling during diastole (reduced preload). Imaging studies have shown similar findings in patients with subclinical hypothyroidism [99, 100, 102, 170]. These patients had a prolonged isovolumetric relaxation time and impaired peak filling rate [99, 100, 102, 170], which are major indicators of diastolic function as they determine ventricular filling. Other parameters that are detrimentally affected in patients with subclinical hypothyroidism include an increased peak A wave velocity, a decrease in early diastolic mitral flow velocity/late diastolic mitral flow velocity (E/A) ratio, and altered mitral acceleration and deceleration times [100, 170, 171]. Moreover, people with mild thyroid hormone deficiency (or subclinical hypothyroidism) have an increased risk of developing HF [86, 107].

In HF, the intracellular milieu of cardiomyocytes is affected by hypoxia, which in turn leads to inflammation [172]. The hypoxia and the inflammatory response reduce deiodinase activity in the cardiomyocyte, which along with reduced plasma T3 levels, result in a decrease in intracellular T3 bioavailability [35]. This lack of T3 is further compounded by an increase in DIO3 gene expression under hypoxic conditions, as the increase in DIO3 activity leads to degradation of T3 into inactive iodothyronines [172]. Therefore, the general picture of the cardiomyocyte in HF is that of an intracellular environment with a reduced availability of T3 and, consequently, reduced metabolism. Whether the low T3 state inside the myocardium in patients with HF is beneficial or harmful is unclear [173]. Subclinical hypothyroidism and low T3 syndrome are the most frequent thyroid hormone alterations in HF [174]. In particular, low T3 syndrome -- secondary to peripheral dysregulation of the conversion of T 4 into T3 , and characterized by low serum T3 , high circulating levels of reverse T3 (rT3 ), and normal T4 and TSH plasma concentrations -- occurs in almost 20-30% of patients with HF [175]. Low T3 syndrome and subclinical hypothyroidism have been associated with a worse prognosis in HF [81, 176, 177]. In particular, the prognostic power of low T 3 syndrome was independent and additive with respect to conventional clinical and cardiac variables, such as left ventricular ejection fraction [175]. Furthermore, the negative prognostic power is increased in patients with high concentrations of B-type natriuretic peptide, in both acute decompensated and chronic compensated HF [175, 178, 179].

Similarly to interventional trials in nonthyroidal diseases, several short-term studies of T3 in patients with HF are available. A study in patients with HF published in 1998 showed that treatment with T3 intravenously for 12 h increased cardiac output and reduced peripheral vascular resistance [180]. In another study, infusion of T3 for 72 h in patients with HF and low T3 had beneficial effects with regard to the pathological neurohormonal stimulation, because T3 therapy reduced aldosterone, renin, and noradrenaline levels, and increased stroke volume, assessed by cardiac magnetic resonance scanning [181]. By contrast, infusion of T3 for 6 h in brain-stem-dead cardiac donors did not improve haemodynamic performance [182]. In the longest trial on T3 therapy in patients with HF, 3-month oral T3 therapy in patients with stable chronic HF and low serum T3 levels had no benefit on left ventricular function, as assessed by radionuclide ventriculography [183]. However, this study was small (only 13 patients completed the trial) and, therefore, was not powered to detect significant differences. Nevertheless, the patients had a 3% improvement in left ventricular ejection fraction [183]. Studies on both the short-term and medium-term effects of levothyroxine therapy in small samples of biochemically euthyroid patients with dilated cardiomyopathy showed that levothyroxine treatment improved left ventricular ejection fraction and cardiac exercise ability, and decreased diastolic dimensions and systemic vascular resistance without causing adverse effects [184, 185]. However, owing to the impaired conversion of T4 to T3 in pathological states, T4 might not be the most suitable first line therapy in such conditions [186].

On the basis of the available data, thyroid hormone replacement therapy should be considered in patients with HF with an altered thyroid profile: low T3 syndrome and/or subclinical hypothyroidism ([Box 4]). The goal should be to restore and maintain both biochemical and clinical euthyroid states. Supraphysiological doses (that is, 'pharmacological' hyperthyroidism) should be avoided because of the potential dangerous effects of this condition. Until results from large, randomized clinical trials are available to confirm long-term safety and efficacy, the suggested substitutive dose of T3 should not exceed 0.2-0.4 [mu]g/kg per day (that is, 15-30 [mu]g per day, divided in two or three administrations) and about 1 [mu]g/kg per day for levothyroxine (that is, 50-100 [mu]g once daily).

Pericardium and epicardium

In addition to myocardial involvement, thyroid disease -- mainly severe hypothyroidism -- can also affect the pericardium by causing pericardial effusion, which in turn can lead to cardiac compromise. Numerous cases of hypothyroidism causing cardiac tamponade have been reported in the literature [187]; however, this situation is rare. Prevalence of pericardial effusion in severe hypothyroidism is thought to be 3-6% [188]. The exact mechanism of pericardial fluid accumulation in these patients is not entirely clear, although the high cholesterol content in the exudative fluid indicates increased capillary permeability and reduced lymphatic drainage from the pericardial space [188, 189].

Epicardial fat tissue has been suggested as a possible cardiovascular risk factor [190, 191], because of the abnormal production of adipocytokines in this tissue [192]. Several observational reports show that patients with thyroid disease have abnormal epicardial fat tissue [193, 194]. However, the clinical significance of these abnormalities is unclear.

Cardiac surgery

Multiple studies have demonstrated a decrease in thyroid hormones after CABG surgery [58, 195, 196]. An open-label study showed a reduction in mortality in patients treated with T3 during CABG surgery [197]. In a study on the prognostic value of low thyroid hormones in patients undergoing CABG surgery [198], consecutive patients undergoing this procedure had their preoperative T3 levels assessed, and baseline T3 was correlated with cardiac output and death. The study showed that suppressed T3 was a strong predictor of death and reduced cardiac output in patients who underwent CABG surgery [198]. In a randomized, placebo-controlled study in patients with impaired left ventricular function undergoing CABG surgery, intravenous injection of T3 increased cardiac output and decreased systemic vascular resistance and frequency of AF after surgery compared with placebo [58, 199]. However, overall outcomes and the need for inotropic support were similar in both groups [58, 199].

Children can develop a sick euthyroid state in the postoperative period of cardiac surgery [200]. A randomized, placebo-controlled study showed that intravenous T3 was safe, had no adverse effects, and significantly reduced the time to extubation in patients aged <5 months undergoing cardiac surgery compared with placebo [201]. In addition, T3 -treated patients needed less inotropic support and had an improvement in left ventricular function compared with patients receiving placebo [201]. A small study in paediatric patients after cardiac surgery (n = 14) did not show any significant difference in outcomes with T3 therapy compared with untreated patients, but did show reduced inotropic support in the T3 -treated patients [202].

Although these studies demonstrated the positive effects of thyroid hormone replacement in patients undergoing cardiac surgery without major adverse effects such as arrhythmias, we should also be aware of the limitations of this therapy. First, the small number of patients in some of the trials means that more evidence is needed before any conclusions on the safety profile of thyroid hormone therapy in such patients can be made. Second, a selection bias cannot be overlooked, because the patients enrolled in these studies were clinically stable and did not have severe left ventricular dysfunction. Therefore, such therapies are probably contraindicated in patients with worse left ventricular function and haemodynamic instability, which poses the risk of arrhythmias. Third, repeat thyroid profiling is an important issue. Results of repeat thyroid function tests after thyroid replacement therapy are not reported in some studies; therefore, we do not know whether such haemodynamic changes could have been caused by thyrotoxic cardiovascular changes.

Acute myocardial infarction

Severe illnesses can have a major effect on the thyroid hormone status, even in people with otherwise normal thyroid function. This effect is best illustrated in the period after MI, in which a transient decrease in serum concentrations of thyroid hormones occurs [203]. The changes in thyroid hormone levels are rapid during the initial 72 h after pain onset, with maximal changes observed between 24 h and 36 h [203]. The main thyroid abnormality is low T3 syndrome, which is present in 15-20% of patients with acute MI [204, 205]. Subclinical hypothyroidism is observed in almost 10% of patients with acute MI [206]. However, serum TSH levels can rise transiently during the recovery phase of nonthyroidal illness, and because the time interval between the acute MI and thyroid hormone testing was not reported in these studies, whether the mildly raised levels of serum TSH occurred before the acute MI, or were a consequence of it, is unclear. Changes in circulating thyroid hormone parameters after acute MI are a result of increased DIO3 activity and reduced DIO1 and DIO2 activity [207, 208]. Thyroid abnormalities following acute MI have traditionally been interpreted as an adaptive process that helps to reduce catabolism and, therefore, to conserve energy [209]. However, this theory is challenged by clinical outcome data on baseline thyroid hormone dysregulation in patients with acute MI. Altered thyroid profile in an acute MI setting is associated with a more severe clinical state and with poorer outcomes [210, 211]. In particular, a greater T3 downregulation has been observed in patients with left ventricular dysfunction, large MI, and intense proinflammatory and stress responses [212]. Furthermore, low T3 and increased rT3 levels at the time of the index acute MI are associated with a higher rate of major cardiac events and are an independent predictor of both short-term and long-term mortality [210, 211]. Furthermore, T3 levels after MI have been shown to correlate strongly with recovery of left ventricular function at 48 h and 6 months after MI, with T3 levels also being an independent predictor of late recovery [213]. These findings have led to interest in assessing the role of thyroid hormones as a therapeutic option for reducing the complications of acute MI.

Cardioprotection and thyroid hormones. Cardioprotection after MI is a new therapeutic target for pharmacological intervention in both the acute and chronic phases of acute MI (when postischaemic HF develops). The main goal of cardioprotective therapies is to reduce or limit myocardial damage in order to avoid impairment of left ventricular function. Furthermore, if and when global left ventricular dysfunction develops, the additional goal of cardioprotective therapies is to limit the progression to irreversible HF syndrome. Myocardial damage in acute MI is caused by two main processes: ischaemic damage owing to the abrupt occlusion of the coronary vascular system, and damage caused by revascularization leading to reperfusion injury. Cardioprotection is a complex phenomenon involving the stimulation of cell growth, neoangiogenesis, and metabolic adaptation, and in which the maintenance of mitochondrial integrity is a new emerging aspect [214]. In the context of cardioprotection after MI, the emerging role of thyroid hormones as an orchestrator of the different molecular, tissue, and cellular elements requires further exploration, particularly with accumulating data on the regenerative properties of thyroid hormones [215, 216]. The aims of cardioprotective therapies with thyroid hormones are to limit infarct extent -- mainly involving the border zone -- and to limit left ventricular postischaemic remodelling -- involving both the border and the remote zones -- through the antifibrotic and proangiogenetic effects of thyroid hormones [214](Fig. 3). This multifaceted role of the thyroid hormones parallels the multifaceted physiopathological mechanisms of postischaemic left ventricular remodelling, which is the final result of molecular, subcellular, cellular, and interstitial processes [217]. Left ventricular remodelling involves changes in cardiomyocytes, extracellular matrix, and microcirculation in the infarct region, the infarct border zone, and remote regions [218, 219]. This remodelling causes thinning of the infarct area, infarct expansion at the site of the necrotic border zone, and hypertrophy and fibrosis of the remote zone [220]. The net final result of this process is progressive left ventricular dilatation, left ventricular functional impairment, and progression to HF [219].

A reduction in T3 serum levels after acute MI is associated with reduced expression of MYH6 and ATP2A2 , whereas the expression of both MYH7 and PLN increases [221]. An improvement in left ventricular and diastolic function after T3 replacement therapy correlates with increased MYH6 and decreased MYH7 [221]. This finding shows that thyroid hormones determine left ventricular function via gene expression [221, 222].

A low T3 state induced by calorie deprivation impairs left ventricular function, in part owing to alterations in both SERCA2 and myosin heavy chain-[alpha] in a manner identical to that in hypothyroidism [223]. T3 supplementation normalizes both cardiac function and phenotype in animal models of calorie deprivation [223], further supporting the role of a low T 3 syndrome in chronic disease states. In acute states, the beneficial effect of thyroid hormones through SERCA2 activation has to be weighed against actions on mitochondrial oxygen demand, because SERCA2 is one of the most sensitive enzymes to ATP depletion [224]. Therefore, mitochondrial dysfunction during ischaemia-reperfusion could undermine calcium removal by SERCA2 and affect myocyte function [224].

Thyroid hormones limit infarct extension by reducing myocyte apoptosis (programmed cell death) through the activation of the cellular prosurvival pathways PI3K/AKTt, protein kinase C [52, 225, 226], and by inhibiting p38 MAPK [227], as shown experimentally in rodent models of acute MI treated with T3 . However, thyroid hormone supplementation has a dose-dependent effect on AKT signalling activation: doses of T3 aiming to normalize plasma T3 levels resulted in improved left ventricular function and left ventricular chamber remodelling, whereas a greater activation of AKT induced by supraphysiological T3 doses led to increased mortality in rodent models [228].

The thyroid hormone system has multiple roles in maintaining mitochondrial integrity. Thyroid hormones are critical regulators of tumour suppressor protein p53 (Ref. 229), a protein that accumulates within the myocardium in the acute phase of MI leading to apoptosis [229]. Experimental studies have shown that the intracellular increase in p53 in cardiomyocytes is more pronounced in rats developing low T3 syndrome early after MI than in those without low T3 syndrome [229]. Early T3 administration blunts the increase of p53 levels in the MI border zone after ischaemia-reperfusion, and this effect is associated with preserved mitochondrial function, decreased apoptosis, and reduced extent of necrosis (premature cell death) in the infarct border zone [229, 230]. In patients who developed de novo HF within 1 year after an acute MI, the levels of the p53-responsive microRNAs, miR-192, miR-194, and miR-34a, were elevated in the early convalescent stage of acute MI, and the levels of miR-194 and miR-34a correlated with left ventricular diastolic dimension [231]. Furthermore, T 3 therapy induces the expression of hypoxia inducible factor 1[alpha] ( HIF1A ), which protects against reperfusion injury [232, 233].

At the level of the remote zone, long-term T4 therapy after MI has beneficial effects on myocyte, arteriolar, and collagen matrix remodelling in the noninfarcted area [234]. A study in animal models showed that oral administration of low-dose T3 after acute MI over a 2-month period improved cardiac structure and function, decreased the incidence of tachyarrhythmias, reduced adverse left ventricular remodelling, and partially restored expression of genes encoding thyroid, mitochondrial, neurohumoral, sarcomeric, ion channel, and fibrotic proteins [235].

The crosstalk between thyroid hormones and inflammatory processes might be relevant in the context of cardioprotection. Continuous activation of the inflammatory system in myocytes has dangerous effects and, importantly, thyroid hormones can modulate the inflammatory and immune response through genomic and nongenomic mechanisms [236]. The nongenomic action of thyroid hormones depends, at least in part, on the interaction with the plasma membrane receptor integrin [alpha]v [beta]3 (to which T4 has a higher affinity than T3 (Refs 41,237)) and the relationship between inflammatory markers and thyroid hormones seems to be mediated through this receptor [236]. In vitro studies have shown that T3 induces an increase in interleukin (IL)-6 and IL-8 in human osteoblastic-like cells and human bone marrow stromal cells [238], whereas in murine dendritic cells, T3 increased IL-12 but not IL-10 (Ref. 239). Notably, in the study in human cells, a supraphysiological dose of T3 (10 nmol/l) was required to obtain the effect, while physiological doses did not induce a response [238].

In the HF setting, the continuous activation of the inflammatory system changes the protective adaptive role of immune responses. Instead of immune responses that promote resistance to myocardial hypoxic injury and induce extracellular matrix remodelling and cell proliferation [240, 241], chronic inflammation leads to dangerous effects for the heart with the induction of apoptosis in myocytes and endothelial cells and, therefore, favouring HF progression [242]. In patients with HF, levels of IL-6 and TNF correlated inversely with those of free T3 , but not with levels of free T4 and TSH [243]. Low T3 circulating levels might depend on inhibition of the peripheral conversion of T4 into T3 following the inhibition of the type 5' deiodinase activity [244]. Although we cannot exclude the possibility that thyroid hormones might be a permissive factor in inflammatory conditions of the heart (pericarditis and myocarditis), additional and more substantial data are necessary.

The above-mentioned clinical observational data, together with experimental evidence [226, 245], indicate the negative effect of an altered thyroid metabolism on cardiac histology, structure, and function, and suggest a possible therapeutic role for thyroid hormones in cardioprotection [29, 246]. However, these observational and experimental animal data need to be confirmed in randomized, controlled clinical trials assessing the efficacy and safety of thyroid hormone replacement therapy. Such evidence in patients with acute MI and with subclinical hypothyroidism and/or low T3 will probably be available in the near future [247, 248]. Moreover, the type of thyroid hormone used (T3 or T4 ), the route of administration (parenteral or oral), the timing in relation to onset of the acute MI, and the duration of therapy need to be defined. Large-scale, phase III and IV studies will be required before the potential benefits of thyroid hormones in patients with acute MI can become part of routine clinical care (Fig. 3).


Clinical and laboratory data provide compelling proof of the role of thyroid hormones in regulating normal cardiac and vascular physiology. Accumulating evidence has increased our understanding of the role of thyroid hormones in cardiovascular disease states at the molecular level. The observation that even minor subclinical alterations in thyroid hormone levels can lead to adverse effects on the cardiovascular system is now recognized. However, whether treatment of mild forms of hyperthyroidism and hypothyroidism can improve cardiovascular outcomes is currently unclear owing to the lack of randomized, controlled clinical trials in this field. Nevertheless, data from observational studies and small, interventional trials assessing cardiovascular risk factors suggest that treating the groups with the highest risk of cardiovascular disease might be beneficial [69]. Similarly, thyroid hormones are affected by cardiac conditions, such as HF and acute MI, and abnormal levels of thyroid hormones might serve as a marker of poor prognosis. Small, short-term clinical trials in HF, and experimental data in animal models of acute MI, suggest that treatment with thyroid hormones is not only safe, but can also be efficacious. However, large, randomized, controlled trials are required before thyroid hormone replacement therapy can become part of routine clinical practice in the management of thyroid dysfunction in cardiac conditions.

Author contributions

All the authors contributed to researching data, discussions of content, writing the article, and to reviewing and editing the manuscript before submission.


Figure 1: Effect of thyroid hormones on the cardiomyocyte via genomic and nongenomic actions. [see PDF for image]

T3 (triiodothyronine) enters the cardiomyocyte through membrane transporters and is also produced in the cell by the conversion of T4 (thyroxine) by type II iodothyronine deiodinase (DIO2). T3 binds to thyroid hormone receptors (TRs) in the nucleus, which in turn regulate transcription by bind to thyroid hormone response elements (TREs) present in regulatory regions of target genes. Thyroxine 5-deiodinase (DIO3) breaks down both T3 and T4 to terminate the action of thyroid hormones. Genes that are positively regulated by thyroid hormones include those that encode myosin heavy chain-[alpha] (MYH6 ) and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 ( ATP2A2 ). Genes that are negatively regulated include those that encode myosin heavy chain-[beta] (MYH7 ) and phospholamban (PLN ). Nongenomic actions of thyroid hormones include regulation of voltage-gated K+ channels, Na+ /K+ ATPase, and the Na+ /Ca2+ exchanger, and activation of survival pathways. AC, adenylyl cyclase; AKT, serine/threonine-protein kinase; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; rT3 , reverse T3 ; T2 , diiodothyronine.

Figure 2: Cardiac 31 P spectra in subclinical hypothyroidism and euthyroid state. [see PDF for image]

a | Cardiac 31 P spectra from a patient with subclinical hypothyroidism before levothyroxine treatment. b | Cardiac 31 P spectra after levothyroxine treatment. c | Cardiac 31 P spectra from a euthyroid individual. The ratio of myocardial phosphocreatine (PCr)/ATP, a marker of mitochondrial function, improves with treatment and is similar to the ratios in the euthyroid control. Adapted with permission from the MD thesis of A. Madathil (Newcastle University, UK). DPG, bisphosphoglycerate; PDE, phosphodiester.

Figure 3: Thyroid hormones and cardioprotection. [see PDF for image]

Schematic representation of the translational potential of the cardioprotective effects of thyroid hormones, with examples of different mechanisms by which thyroid hormones are involved in cardioprotection (demonstrated in the experimental setting) and the potential effects of thyroid hormone replacement therapy for the management of patients with cardiovascular disease (both in the clinical and the epidemiological settings). AKT, serine/threonine-protein kinase; ERK1/2, extracellular signal-regulated kinases 1/2; GSK3[beta], glycogen synthase kinase 3[beta]; HIF1[alpha], hypoxia-inducible factor 1[alpha]; MAPK, mitogen-activated protein kinase; mir, microRNA; mitoKATP , mitochondrial ATP-sensitive potassium channel; mTOR, serine/threonine-protein kinase mTOR; PI3K, phosphatidylinositol 3-kinase; TGF[alpha], transforming growth factor-[alpha].

Table: Causes of abnormal thyroid function in nonpregnant adults [see PDF for image]

Table: Effects of subclinical thyroid diseases on cardiovascular risk factors [see PDF for image]

Box 1: Thyroid hormone system

* The thyroid gland produces T3 (3,5,3'-triiodothyronine) and T4 (3,5,3',5'-tetraiodothyronine; also known as thyroxine)

* T3 is considered the biologically active hormone; T4 must be converted to T3 to produce potent thyroid hormone receptor-mediated effects

* The majority of T3 is produced by extrathyroidal deiodination of T4 to T3 ; therefore, deiodinating enzymes have an essential role in regulating tissue thyroid hormone levels

* In the cardiomyocyte, the relevant deiodinating enzymes are type II iodothyronine deiodinase (DIO2) and thyroxine 5-deiodinase (DIO3)

* DIO3 catabolizes both T3 and T4 to inactive products, thereby terminating the thyroid hormone action

* Thyroid hormones have cardiac chronotropic and inotropic effects

Box 2: Overt and subclinical hyperthyroidism

* Overt hyperthyroidism is defined by suppressed serum TSH and high thyroid hormone levels (above the laboratory reference range)

* Overt hyperthyroidism can be caused by stimulation of the thyroid-stimulating hormone (TSH) receptor by autoantibodies (Graves disease) or by autonomous production of thyroid hormones in thyroid nodules [39]

* Prevalence of overt hyperthyroidism in the general population is 0.5% [39]

* Subclinical hyperthyroidism is defined by low TSH serum levels (<0.3 or 0.4 mU/l), with T3 and T4 serum levels within the reference range [67, 68, 69, 70]

* Subclinical hyperthyroidism can be caused by exogenous or endogenous factors

* Prevalence of endogenous subclinical hyperthyroidism in the general, nonpregnant, adult population is 2% [10]

* The risk of atrial fibrillation is increased with both overt and subclinical hyperthyroidism [39]

* Whether subclinical hyperthyroidism is associated with higher cardiovascular morbidity and mortality is uncertain, but international guidelines advocate treatment of hyperthyroidism in those individuals with serum TSH <0.1 mU/l (Ref. 92)

Box 3: Overt and subclinical hypothyroidism

* Overt hypothyroidism is defined by elevated serum levels of thyroid-stimulating hormone (TSH >10 mU/l) and low serum levels of free T 4

* Prevalence of overt hypothyroidism ranges between 0.2% and 2.0% [11, 93]

* Subclinical hypothyroidism is defined by raised serum TSH concentrations with serum levels of thyroid hormones within the reference range. Subclinical hypothyroidism can be mild (TSH >4.0-4.5 mU/l, but <10.0 mU/l) or severe (TSH >10.0 mU/l)

* Prevalence of subclinical hypothyroidism in the general, adult population is 4-20% [69]. Women and old individuals (aged >60 years) are more likely to be affected by subclinical hypothyroidism [97]

* Whether subclinical hypothyroidism is associated with higher risk of cardiovascular disease is unclear. Findings from meta-analyses of observational studies suggest that young individuals (aged <65 years) [110] and those with severe disease (serum TSH >10 mU/l) are at increased risk of cardiovascular disease [108]

* Evidence from several randomized clinical trials show that treatment of subclinical hypothyroidism with thyroid hormones has a modest effect on lipid profiles [124]

* International guidelines suggest that treatment with thyroid hormones should be offered only to those individuals with serum TSH >10 mU/l, symptoms of hypothyroidism, or to those individuals aged <70 years [112]

Box 4: Therapy with thyroid hormones in cardiovascular disease

Heart failure

* Thyroid hormone replacement therapy should be used only in patients with an altered thyroid profile: low T3 syndrome and/or subclinical hypothyroidism

* The goal should be to restore and maintain biochemical and clinical euthyroid states

* Supraphysiological doses (that is, 'pharmacological' hyperthyroidism) should be avoided

* The suggested dose of T3 should not exceed 0.2-0.4 [mu]g/kg per day (that is, 15-30 [mu]g per day, divided in two or three administrations)

* The suggested dose of levothyroxine is 1 [mu]g/kg per day (that is, 50-100 [mu]g once daily)

Cardiac surgery

* Serum thyroid hormone levels, particularly T3 , decrease after cardiac surgery -- probably as part of the nonthyroidal illness syndrome

* Preoperative low T3 levels are associated with worse morbidity and mortality after cardiac surgery [198]

* Short-term T3 therapy in patients with impaired cardiac function who are undergoing CABG surgery leads to a transient improvement in cardiac function, but has no effect on the requirement for inotropic support or on perioperative morbidity and mortality [58]

* T3 therapy is safe in children undergoing cardiac surgery, and might be beneficial in certain subgroups (such as those aged <5 months) [201]

* Studies with longer duration and including a larger number of participants are required to assess the safety and effectiveness of T3 therapy in cardiac surgery

Acute myocardial infarction

* Altered thyroid hormone metabolism after myocardial infarction (MI) negatively affects cardiac structure and function

* Thyroid hormones have an important role in postischaemic left ventricular remodelling and in limiting infarct size owing to their antifibrotic and proangiogenic properties [214]

* T3 therapy in animal models of MI improves left ventricular function [226]

* Thyroid hormones maintain mitochondrial integrity and are critical mediators in ischaemia-reperfusion injury [229]

* The utility of thyroid hormone therapy in the management of MI is being evaluated in early-phase clinical trials and, if these trials show promise, larger, phase III and IV studies will be required before such therapy can become part of routine clinical care


S.R. is supported by a National Institute for Health Research (NIHR) Career Development Fellowship. The work of S.H.S.P. on subclinical hyperthyroidism was funded by MRC Grant G0500783. This report is independent research supported by the National Institute for Health Research Career Development Fellowship CDF-2012-05-231. The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health.


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Author Affiliation(s):

[1] Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.

[2] Freeman Hospital, Freeman Rd, High Heaton, Newcastle upon Tyne NE7 7DN, UK.

[3] Clinical Physiology Institute, CNR, Via Moruzzi 1, 56124, Pisa, Italy.

[4] Department of Endocrinology, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK.

[5] Gateshead Health NHS Foundation Trust, Saltwell Road South, Gateshead NE8 4YL, UK.

Correspondence: [1] Email:

Author Bio(s):

Avais Jabbar is a clinical research fellow at The Freeman Hospital Cardiothoracic Centre, Newcastle upon Tyne, UK. After completing his basic medical training in 2009 from Barts and the London School of Medicine and Dentistry, London, UK, Dr Jabbar is undertaking a National Institute of Health Research (NIHR) project investigating subclinical hypothyroidism after myocardial infarction. He has also completed a Bachelor of Medical Sciences in molecular therapeutics investigating the prophylaxis of venous thromboembolism.

Alessandro Pingitore graduated in Medicine and Surgery in 1991, received a PhD in cardiovascular physiopathology in 1997, and later undertook postgraduate training in cardiovascular disease. Dr Pingitore is a permanent scientist of the National Research Council Institute of Clinical Physiology (CNR-IFC), Pisa, Italy. His research interests are the assessment of cardiac function with noninvasive imaging and the relationship between thyroid and heart. Currently, he is studying the physiological response to strenuous physical stress in normal or extreme environments, and the role of social networks on public health and cardiovascular disease prevention. Dr Pingitore is author of 128 articles published in international peer-reviewed journals, two books, and 10 book chapters.

Simon H. S. Pearce is Professor of endocrinology at Newcastle University, UK, and Honourary Consultant Physician at the Royal Victoria Infirmary, Newcastle upon Tyne, UK. Professor Pearce qualified in Medicine MBBS with 1st class honours from Newcastle University. Following internal medicine training, he undertook postgraduate training in endocrinology at the Royal Postgraduate Medical School, Hammersmith, London (MD degree awarded with distinction), at the Brigham & Women's Hospital, Boston, USA, and as a Wellcome Trust Advanced fellow in Newcastle, UK. He was appointed Senior Lecturer in Endocrinology in 2001 at Newcastle University, and promoted to Professor in 2007, affiliated to the Institute of Genetic Medicine. Professor Pearce serves as current Programme Secretary for the Society for Endocrinology, and on the editorial boards of the Journal of Clinical Endocrinology & Metabolism , European Thyroid Journal , and BMC Thyroid Research . The main themes of his research programme are in regenerative medicine approaches to adrenal failure, genetics of autoimmune endocrine disease, and long-term management of thyroid diseases. He has published >150 articles, with a current H-index of 45.

Azfar Zaman is Clinical Professor of Cardiology at Freeman Hospital and Newcastle University, Newcastle-upon-Tyne, UK. He is Head of Coronary Intervention and Director of the Cardiac Catheter laboratories at Freeman Hospital. As Clinical Director for Cardiovascular Research, his research interests focus on patients with atherothrombosis and diabetes. He has research grants from the British Heart Foundation, Diabetes Wellness Research Foundation, and the National Institute of Health Research (NIHR). He has >100 peer-reviewed publications, and leads a team of 16 individuals conducting clinical trials and research in cardiology.

Giorgio Iervasi is Director of the National Research Council Institute of Clinical Physiology (CNR-IFC), Pisa, Italy. Dr Iervasi was Senior Researcher at CNR-IFC from 2007 until 2014, and Research Director of the CNR-IFC from 2007 until 2014. In 2011-2014, he was Head of the Cardiovascular Endocrinology and Metabolism Clinical & Experimental Unit at the CNR/Tuscany Region G Monasterio Foundation, Italy. Over the past 30 years, his research activity has focused in the cardio-endocrine metabolic field, with the use of interdisciplinary and translational approaches. His initial studies included development and implementation of novel multitracer methods for in vivo modelling of thyroid hormones and cardiac peptide metabolism in humans. These new methodologies were subsequently applied to pathophysiological studies investigating the role of altered thyroid hormone and/or cardiac peptide metabolism in cardiac disease, with a special focus on heart failure progression in humans. In the past 15-20 years, Dr Iervasi mostly focused on understanding the pathogenic role and clinical implications of mild thyroid dysfunction on cardiac disorders, with particular attention to low T 3 . His major long-term goal is to provide evidence on the unresolved issue of low T3 resulting from cardiac dysfunction is not protective but maladaptive. Dr Iervasi is author of >200 publications.

Salman Razvi is a Senior Clinical lecturer at Newcastle University, Newcastle upon Tyne, UK, and Consultant Endocrinologist at Queen Elizabeth Hospital, Gateshead, UK. He was awarded an MD degree (with commendation) from Newcastle University in 2006 for a clinical research project investigating endothelial function in patients with subclinical hypothyroidism. He went on to complete his specialist training in Diabetes and Endocrinology in the North East of England Deanery in 2007. His main research interests continue to focus on the cardiovascular aspects of thyroid disease, and he has been an invited speaker at several national and international meetings on this topic. Dr Razvi has recently been awarded the prestigious National Institute of Health Research (NIHR) Career Development Fellowship and he is investigating the role of thyroid hormones in the management of subclinical thyroid disease at the time of an acute myocardial infarction. He serves on the editorial panel of the journal Thyroid , and has been on the executive committee of the British Thyroid Association.

Article history:

Published online: 11/04/2016

DOI: 10.1038/nrcardio.2016.174

Source Citation (MLA 8th Edition)

Jabbar, Avais, et al. "Thyroid hormones and cardiovascular disease." Nature Reviews Cardiology, vol. 14, no. 1, 2017, p. 39+. Academic OneFile, Accessed 22 Apr. 2018.


Thank you. And I think you might just be due a prize for the longest single reply ever posted here. :-)

Quoting from that:

Unfortunately, the role of subclinical thyroid disease as a cardiovascular risk factor is underrecognized, owing to the lack of high-quality outcome trial data to guide practice after the abnormal thyroid function is identified, and because of the lack of commercial exploitability.


Well found! I like the fact that one of the authors is an endocrinology professor. Maybe he will have some influence on his colleagues!!!


Wow! Thank you Astridnova. And thank you helvella for the prompt.

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Astridnova Thank you so much for sharing this absolutely fascinating research article.


Gosh, thanks for that. It’s going to take me a while to read it properly. When people say that if you have one condition (aka diagnosis) then you are more susceptible to have others, then you start wondering about the interrelationship. I’ve found it hard enough understanding the thyroid bits (TRH, TSH, T4, T3 and any I’ve missed). But this shows that it affects cardiovascular as well and mentions that there are T3 and T4 receptors in all parts if the body. No wonder blood pressure and cholesterol levels can be affected and in my case probably blood glucose as well!

So do we treat symptoms or diseases or a combination if both. Fascinating stuff. I can’t think why researchers aren’t interested just because they can’t see the immediate financial benefit....

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Yep my mum has hyperthyroidism and has copd and ........ you’ve guessed it heart failure as written above after years of not being treated.

Can’t wait for my turn.

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Fascinating. I did not understand it all, but what I did understand was illuminating. I hope this might indicate a trend to take thyroid conditions more seriously.

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Perhaps Dr Malcolm Kendrick could be persuaded to look at this as part of his current CVD series of blogs.


Was rather assuming he would have seen it. But that is silly - good idea to draw his attention to it.


I've just sent the entire text to him, asking if he will cover the subject. Have asked him before already.


I posted a comment on his blog asking him to cover the thyroid factor.


He did a post once - Stop Treating Thyroid Patients like Children. Of course the Thyroid Heart connection would be great. I think he once commented that he needed to finish - What really causes heart disease - before embarking on the thyroid.

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Yes I saw that one and got excited that he would cover the topic... Fingers crossed! :)


When oh when will all Specialists sit down in one room and join up the dots .... Thank you for posting ...


The worrying thing is that you probably could fit all those who really understand into one room. :-(


.... and a small one at that 😊


Wow! Helvella thank you so much for that most interesting research article.


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