Acute coronary syndrome (ACS), the most severe ischemic heart disease, has been recognized as one of the major causes of mortality globally and considered to be a serious public health problem. Despite the increased number of therapeutic interventions performed in patients with ACS, such as advanced pharmacotherapy and myocardial reperfusion therapy, there is still a significant incidence of major adverse cardiovascular events in these patients. Identifying the risk factors that affect the prognosis of ACS patients, is therefore, of great importance.

Homeostasis of thyroid hormones has a significant impact on the cardiovascular system [1, 2]. The abnormalities of thyroid function, subclinical or overt hypothyroidism and hyperthyroidism, have been associated with the progression of atherosclerosis and increased cardiovascular morbidity and mortality in patients with coronary artery disease (CAD) [2, 3, 4, 5, 6]. Serum triiodothyronine (T3), which is the principal bioactive thyroid hormone for cardiomyocytes, has an effect on myocardial contractility, systemic vascular resistance and cardiovascular hemodynamics. T3 works mainly through the modulation of the relative proteins coded by target genes in the cardiovascular system such as myosin heavy chains, sarcoplasmic reticulum proteins, and calcium-activated ATPase (Ca${}^{2+}$-ATPase) [7]. Lower free triiodothyronine (FT3) levels are associated with a worse prognosis in acute or chronic diseases, for instance, myocardial infarction (MI) and chronic heart failure (HF) [8, 9].

Although previous studies have found that lower FT3 level have a close relationship with major adverse cardiovascular events (MACE) in ACS patients, the relationship between the level of FT3 and adverse cardiovascular events in such patients undergoing PCI has not been defined. Therefore, our study aimed to investigate the association between FT3 level and adverse cardiovascular events in patients with ACS undergoing PCI.

The present study retrospectively investigated the predictive value of FT3 levels for adverse cardiovascular events in ACS patients undergoing PCI. The major findings are: (1) compared with the highest level of FT3, those with lower FT3 levels had a significantly higher incidence of MACE; (2) decreased FT3 levels were an independent predictor of poor prognosis; (3) there was a non-linear association between FT3 level and MACE, and unplanned repeat revascularization, but not with all cause death, ischemic stroke and MI; (4) the additional prognosis value of the baseline risk model was found after adding the tertiles of each FT3 level.

Thyroid hormone has a direct effect on the cardiac, and is an important regulator of cardiac function and hemodynamics [2]. Thyroid hormones affect cardiac status: (1) by direct genomic actions on cardiomyocytes via binding to nuclear receptors, which regulates the expression of target genes encoding sodium/potassiumtransporting ATPases, $\alpha$-myosin heavy chain and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), and negatively regulates the transcription of $\beta$-myosin heavy chain and phospholamban (PLN); (2) by non-genomic actions on the ion channels for sodium, potassium and calcium and influence various intracellular pathways of cardiomyocytes and vascular smooth-muscle cells, which determines cardiovascular haemodynamics, and cardiac contractility [7, 11, 12, 13, 14]. T3 and T4 are the two main iodinated hormones that are secreted by thyroid gland, and both can generate biological effects by combining the thyroid hormone receptors. There is a tenfold greater affinity of the thyroid hormone receptors for T3 compared to T4 [2, 15]. Therefore, T3 is universally regarded as the biologically active form of thyroid hormone.

Thyroid hormone metabolism disorders increase the risk of CAD and cardiovascular death, therefore evaluation of FT3 levels may benefit to identify patients who are susceptible to cardiovascular disease [16, 17, 18]. Therefore, assessment of FT3 levels has important clinical significance for risk stratification and individualized treatment of such patients.

Previous studies have found that patients with overt hyperthyroidism present with hyperdynamic circulation, such as increased cardiac preload and contractility, decreased systemic vascular resistance, increased heart rate, increased systolic blood pressure and pulmonary hypertension, while overt hypothyroidism is associated with a reduction in cardiac output and cardiac contractility, decreased heart rate, increased peripheral vascular resistance, dyslipidemia, and atherosclerotic plaque development and instability [1, 4, 5, 11]. Both overt hyperthyroidism and hypothyroidism are significantly associated with a higher incidence of adverse cardiovascular events [19, 20, 21, 22]. Even CAD patients with mild thyroid dysfunction and subclinical hyperthyroidism may also experience adverse cardiovascular events, such as supraventricular tachyarrhythmias, especially atrial fibrillation [23], and subclinical hypothyroidism is a strong indicator for the risk of atherosclerosis and myocardial infarction [1, 24, 25], both of which may markedly increase cardiovascular morbidity and mortality.

Several studies have shown a significant correlation between FT3 levels and adverse cardiovascular events. Lower FT3 levels have been correlated with HF, lower LVEF and serum biomarkers of myocardial injury, such as troponin T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) [26, 27]. Lymvaios et al. [28] found a significant correlation of low T3 with impaired ventricular function in patients with acute MI (AMI), and that T3 levels appear to be an independent predictor of late functional recovery. In addition, D. H. Kim et al. [29] reported that in STEMI patients, the degree of transmural involvement accessed by contrast-enhanced cardiac magnetic resonance (CMR) imaging is strongly correlated with T3 levels. Chang et al. [30] demonstrated that low FT3 levels was an independent indicator of long-term worse prognosis in STEMI patients undergoing PCI. Other studies also found that low T3 levels have been correlated with short and long-term mortality in STEMI patients undergoing PCI [9, 31]. Similar to patients with STEMI, NSTE-ACS patients with low FT3 levels had an increased risk of mortality during 1-month and 1-year follow-up [17]. Furthermore, reverse T3 (rT3) was independently associated with 1-year mortality [32]. In most of the above studies, PCI was not performed in all the study populations; therefore, whether PCI combined with the FT3 level improves the prognostic value of the baseline risk factors is controversial. Our study is unique in that all patients received PCI, and therefore allowed us to assess the prognostic value of the FT3 level and its incremental effect on risk stratification based on traditional risk factors in these patients.

In the study, we found that low FT3 has an impact on cardiovascular system and clinical outcomes. However, there are a large number of factors contributing to low FT3, such as demographic factors (age, gender and BMI [33, 34, 35, 36]), lifestyle factors (alcohol consumption [37]), diet (soy-based food [38, 39], olive oil [40]), exercise [41, 42], pollutants (chemicals and heavy metals) [43]. We also found that age, gender and BMI, which were all associated with low FT3, were significantly different from MACE. Besides, after multivariate analysis, decreased FT3 levels were an independent predictor of poor prognosis.

Rapid down-regulation of the thyroid hormone system in patients with acute myocardial ischemia might be of great help to reducing oxygen demands on the myocardium. Several studies confirmed that the function of pituitary gland and the release of TSH could directly affected by cytokines, such as Interleukin-6 (IL-6), tumor necrosis factor-$\alpha$ (TNF-$\alpha$), and interferon-$\gamma$ (INF-$\gamma$) [44, 45, 46]. L. Friberg, S et al. [47] prospectively revealed that patients with angina had lower T3 levels, smaller infarctions, and higher levels of C-reactive protein and interleukin 6 (IL-6). The low T3 syndrome might be a beneficial and physiological adaptation to early stress response of the ACS [48, 49]. However, this view has been questioned in the past several years, and low T3 syndrome may not only be an adaptive response to cardiovascular diseases [50]. There are several possible mechanisms. First, T3 was the major thyroid hormone. Low T3 or FT3 in patients with low T3 syndrome can lead to the progression of cardiovascular diseases, worsen cardiac structure and function, and increased the risk of mortality [46, 51]. Second, low T3 syndrome remains an independent prognostic factor in cardiovascular patients even after the adjustment of traditional risk factors. These results indicate that there is a direct link between low T3 syndrome and mortality risk in these patients rather than an adaptive response [52]. Third, clinical and experimental studies have reported that in cardiovascular patients or animal models, T3 treatment can produce a beneficial effect on cardiac function [53, 54]. Finally, previous studies revealed that decreased thyroid levels might have existed before the infarction occurred [47]. This suggests that there is a relationship between the alteration of T3 levels and cardiovascular diseases. Lower T3 levels depress cardiac function, and cardiovascular diseases may result in lower T3 levels. As a result, a persistent down-regulation of thyroid function might be maladaptive in cardiovascular patients. Several studies have shown that ACS patients diagnosed with the low T3 syndrome have poorer cardiovascular outcomes [31, 55, 56].

Previous studies have demonstrated that lower FT3 levels have adverse prognostic value for ACS patients undergoing PCI. Therefore, incorporating assessment and intervention of thyroid function into long-term management might be beneficial to these patients. F. Forini et al. [54] found that long-term L-T3 replacement in a rat model after MI reduces the infarct size by 50% and prevents the progression to HF. K. K. Henderson et al. [57] revealed that T3 treatment to euthyroid levels improves systolic function, and tends to improve diastolic function in an animal model of myocardial infarction-induced HF. In clinical studies, J. D. Klemperer et al. [58] found that raising serum T3 concentration in patients undergoing coronary artery bypass surgery improves cardiac function, but there was no significant difference in outcomes. A double-blind, randomized, placebo-controlled trial found that treatment with T3 in children after cardiopulmonary bypass operation improves myocardial function [53]. A recent RCT found that compared with placebo, patients with subclinical hypothyroidism and acute MI treated with Levothyroxine did not improve LVEF during a 52-week follow-up period [59]. The therapeutic mechanisms of action of TH are not well studied in humans, but in vitro and in vivo disease models have provided important knowledge of its repair and regeneration properties. The TH signaling pathway is a universally conserved pathway with pleiotropic effects that regulates biological development, metabolism and homeostasis, as well as having an important effect in tissue repair/regeneration. Indeed, a growing number of experimental and clinical studies suggest that TH may be critical for recovery after injury. Katzeff H L et al. [60] revealed that T3 can activate Akt signaling in rat cardiomyocytes, which protects myocytes against serum starvation-induced cell death, and also found that T3 supplementation protected myocytes against ischemic-induced apoptosis, which may be mediated by Akt signaling [61]. In an ischemia/reperfusion model, Pantos et al. [62] demonstrated that T3 administration had an anti-apoptotic effect associated with lower levels of p38 mitogen-activated protein kinase (MAPK). Several studies illustrated that L-T3 therapy increases the expression of hypoxia-inducible factor-1$\alpha$ (HIF-1$\alpha$) and mitochondrial transcription factor A (mt-TFA), which have an important role in maintaining cell survival during myocardial ischemia, attenuating left ventricular remodeling and preserving post-MI cardiac performance [63, 64, 65]. Inhibits the expression of thyroid hormone receptors (TRs) can activate to normal and facilitate the adult transcriptional phenotype under pathological conditions by administrating TH, which might be relevant to therapeutic interventions [66, 67]. In addition, TH appears to regulate the differentiation of cardiac cells (e.g., regulation of contractile proteins and protein kinases, cytoskeletal orientation and cell geometry) and the cellular response to stress [68, 69, 70]. Whether T3 supplementation can benefit patients with ACS undergoing PCI and the therapeutic mechanism of TH are still unknown. The Thyroid Hormone Replacement therapy in ST elevation myocardial infarction (THiRST) trial, an ongoing RCT, was designed to further evaluate the effect of T3 treatment in patients with AMI [65], and the results of this study are noteworthy. Future RCTs will be designed to further evaluate the effect of T3 treatment in patients with ACS.

In ACS patients undergoing PCI, the present study revealed that decreased FT3 levels was significantly associated with a worse prognosis. There was a non-linear association between FT3 and MACE, all-cause death and unplanned repeat revascularization. The addition of FT3 levels to the baseline risk model significantly improved the ability for risk prediction. Additional large scale randomized studies are needed to confirm whether FT3 levels have a positive effect on improving clinical outcomes.

FT3, free triiodothyronine; BMI, body mass index; CAD, coronary artery disease; CKD, chronic kidney disease; MI, myocardial infarction; PCI, percutaneous coronary intervention; PAD, peripheral artery disease; LVEF, left ventricular ejection fraction; SBP, systolic blood pressure; HR, heart rate; GRACE, global registry of acute coronary events; ACS, acute coronary syndrome; UA, unstable angina pectoris; MI, myocardial infraction; NSTEMI, non-ST segment elevation myocardial infarction; STEMI, ST segment elevation myocardial infarction; TSH, thyroid stimulating hormone; FT4, free thyroxine; hsCRP, high-sensitivity C-reactive protein; TG, triglycerides; TC, total cholesterol; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; FPG, fasting plasma glucose; LM, left-main; LAD, left anterior descending; SYNTAX, SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery; DES, drug eluting stent; BRS, bioresorbable scaffold; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; MACE, major adverse cardiovascular events; eGFR, estimated glomerular filtration rate; HR, hazard ratio; CI, confidence interval; Ref, reference.

Conceptualization, ZQY and QYS; methodology, ZQY, XTM and JL; software, ZQY; validation, QXL, YFW and XLL; formal analysis, ZQY and ZJW; investigation, DMS; resources, ZJW; data curation, ZQY and XTM; writing—original draft preparation, ZQY; writing—review and editing, ZF and ZJW; supervision, HS and ZJW; project administration, ZF and ZJW; funding acquisition, ZJW and YJZ. All authors have read and agreed to the published version of the manuscript.

This study was conducted in accordance with the guidelines of the Declaration of Helsinki and approved by the institutional review board of Beijing Anzhen Hospital, Capital Medical University (Ethic approval number: 2016034x). Given the retrospective nature of this study, the requirement for informed consent was waived.

We would like to express our gratitude to all those who helped us during the writing of this manuscript, and thanks to all the peer reviewers for their opinions and suggestions.

Project funded by National Key Research and Development Program of China (2017YFC0908800, Yu-Jie Zhou), Beijing Municipal Administration of Hospitals’ Mission plan (SML20180601, Yu-Jie Zhou), China Postdoctoral Science Foundation (2021M692253, Xiao-Teng Ma), Beijing Postdoctoral Research Foundation (2021-ZZ-023, Xiao-Teng Ma), Beijing Municipal Health Commission (Jing 19-15, Hua Shen), Beijing Municipal Health Commission (2022-2-1052, Zhi-Jian Wang).

The authors declare no conflict of interest.