Background
Despite the use of novel treatment strategies, patients with acute myocardial infarction (AMI) still suffer from an adverse prognosis [
1]. Attention should still focus on revealing novel treatment targets and important risk factors. In AMI, serum triiodothyronine (T3) is decreased [
2‐
5], while serum thyroxine (T4) remains almost unchanged [
2‐
4] or declines [
5]. In fact, the cardiovascular system is the foremost target of thyroid hormones, and is adversely affected even if these hormone levels only change slightly [
6]. A decrease in serum T3 has been found to be a predictor of larger myocardial injury size [
4,
5,
7], worse cardiac function [
8,
9], greater thrombus burden [
10], and a poorer prognosis [
5,
11‐
14] in AMI. A recent study also confirmed the association between free T4 and adverse outcomes in acute coronary syndrome [
15]. Serum T3, which is the most important bioactive thyroid hormone for cardiomyocytes, is mostly produced by the peripheral process of deiodination of T4 [
6]. In AMI, the studies have suggested that the peripheral conversion of T4 into T3 was reduced [
3,
4]. However, no previous study has focused on the clinical value of the disturbance of the conversion of T4 into T3 in patients with AMI. The fT3/fT4 ratio, a thyroid hormone index, could reflect deiodinase activity [
16], and thus, represent the conversion of T4 to T3 [
17]. The Global Registry of Acute Coronary Events (GRACE) score is widely recommended to calculate in-hospital and long-term mortality in acute coronary syndrome (ACS), which helps clinical decision-making and discriminates high-risk patients [
18‐
22]. The GRACE score has passed rigorous validation since its conception in 2004; however, several changes has been approved in the diagnostic and management tools of ACS in the last 14 years. Moreover, the estimation of risk is a continuous process, and further refinement of current risk scores may help the decision-making process in real world practice. Furthermore, novel risk factors are not included in the GRACE score, such as thyroid hormone-related indicators including thyrotropin, fT3, fT4 and the fT3/fT4 ratio.
In the present study, we aimed to assess whether the fT3/fT4 ratio is a useful clinical parameter in predicting long-term prognosis in euthyroid patients with AMI undergoing PCI. In addition, we compared the prognostic performance of fT3, fT4, and the fT3/fT4 ratio using the GRACE score as the reference standard. Moreover, we confirmed whether fT3, fT4, and the fT3/fT4 ratio could improve the prognostic performance of the GRACE score.
Discussion
The present study tested the association between the fT3/fT4 ratio and the long-term prognosis in euthyroid patients with AMI undergoing PCI. The main findings were as follows: (1) the fT3/fT4 ratio was an independent predictor of 1-year all-cause mortality; (2) the prognostic performance of the fT3/fT4 ratio was similar to that of the GRACE score, and better than that of fT3 and fT4; and (3) only the fT3/fT4 ratio could improve the prognostic performance of the original GRACE score model.
Thyroid hormones extensively affect the physiological and pathological processes of the cardiovascular system [
6]. Previous studies have demonstrated that even mild thyroid dysfunction in cardiac patients results in an adverse prognosis: subclinical hypothyroidism is a strong indicator of atherosclerosis risk [
28,
29]; subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation [
30]; a mildly altered thyroid status (including subclinical hypothyroidism, subclinical hyperthyroidism, and low T3 syndrome) is also associated with an increased risk of mortality in patients with cardiac disease [
14,
31‐
33]. T3 and T4 are two main iodinated hormones secreted by the thyroid gland. Since the affinity of the thyroid hormone receptors is far higher for T3 than for T4, T3 is considered the biologically active hormone, and T4 must be converted to T3 to produce potent thyroid hormone receptormediated effects [
6]. Less than 20% of circulating T3 is directly secreted by the thyroid gland, while more than 80% is produced by a peripheral process of deiodination of T4 [
6]. Thus, the conversion of T4 to T3 is very important in the production of circulating T3 and the thyroid hormone action on the heart. In chronic and acute illness, this conversion has been reported to decline [
3,
4,
34]. Furthermore, a disturbance in the conversion of T4 to T3 contributes to reduced T3 production in low T3 syndrome and its etiology [
16,
34,
35]. Previous studies have demonstrated that the fT3/fT4 ratio could reflect deiodinase activity [
16], and thus, represent the conversion of T4 to T3 [
17]. A significant correlation between the fT3/fT4 ratio and infarct size has been observed [
4]; however, no study has focused on the clinical value of a disturbance in the conversion of T4 to T3 in AMI patients. The present study demonstrates that in euthyroid patients with AMI undergoing PCI, the fT3/fT4 ratio was associated with 1-year all-cause mortality (all-cause mortality for low the fT3/fT4 ratio group vs the high fT3/fT4 ratio group: 11.8% vs 2.1%,
log-rank test:
p < 0.001). The results of Cox regression multivariate analysis further confirmed that a reduction in the fT3/fT4 ratio was associated with a 2.546-fold greater likelihood of 1-year all-cause death. The discriminative performance of the fT3/fT4 ratio was encouraging (C-statistic: 0.738; 95% CI: 0.709–0.766), far better than that of fT3 and fT4, and similar to that of the GRACE score in predicting 1-year all-cause mortality in euthyroid patients with AMI undergoing PCI. Taken together, the fT3/fT4 ratio is a very useful clinical parameter in predicting long-term prognosis in euthyroid patients with AMI undergoing PCI, can help risk stratification in AMI patients, and identify those patients at high risk of 1-year all-cause death. Therefore, the fT3/fT4 ratio may be taken as a better risk factor for AMI; however, further large cohort studies are needed in this regard.
The GRACE score, containing the main traditional risk factors for cardiovascular disease, was derived in the early twenty-first century. Since then, increasing amounts of novel risk factors have been studied; nevertheless, the GRACE score does not contain any of these new risk factors such as thyroid hormone-related indicators, including thyrotropin, fT3, fT4, and the fT3/fT4 ratio [
6]. The present study found that the fT3/fT4 ratio was a valid adjunct to the GRACE score. The new model, the GRACE score + the fT3/fT4 ratio, showed good discrimination (C-statistic: 0.836), calibration (HL
p-value: 0.180, R
2: 0.157), and precision (Brier score: 0.0348). The prognostic performance of the new model was also better than that of the original model (only the GRACE score). In clinical practice, the new model, the GRACE score combined with the fT3/fT4 ratio, can also help make a more accurate assessment of the long-term mortality risk and more precise clinical decisions.
The present study has several limitations. Firstly, this was a single center, observational study; thus, potential confounders and selection bias could not be completely adjusted, since some important clinical data were collected from electronic medical records. However, it has the advantage of being a prospective study. Secondly, thyroid function tests were not repeated within 2–12 weeks to exclude transient forms of thyroid dysfunction as recommended by the guidelines [
36], at euthyroid diagnosis. Thirdly, previous studies have indicated that iodinated contrast media may influence thyroid function [
37,
38]; however, in the present study, the thyroid function of some patients was tested following the use of iodinated contrast media, since they needed emergency PCI. Fourthly, the present study did not test total T3 (TT3) and total T4 (TT4) levels, since only free T3 and free T4 can enter target cells and play a role, directly reflecting the state of thyroid function [
6]. Fifthly, previous studies have found that reverse T3 increased in AMI [
2‐
5], and that increased levels of reverse T3 were also independently associated with 1-year mortality [
39]; however, the present study did not test reverse T3 (rT3). In the future, other studies should be performed to obtain the association between prognosis and more thyroid hormone-related indicators including TSH, TT3, TT4, fT3, fT4, rT3, and the fT3/fT4 ratio. Finally, the present study only included AMI patients in whom successful PCI was performed; thus, the results cannot be generalized to all ACS patients.