Impact of Persistent Subclinical Hypothyroidism on Clinical Outcomes in Non-ST-Segment Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

Chuyi Han; Kaihang Xu; Le Wang; Yingyi Zhang; Rui Zhang; Ao Wei; Lijie Dong; Yuecheng Hu; Jinghan Xu; Wenyu Li; Tingting Li; Chunwei Liu; Wei Qi; Dongxia Jin; Jingxia Zhang; Hongliang Cong


Clin Endocrinol. 2022;96(1):70-81. 

In This Article


To the best of our knowledge, this is the first study to follow up the changes in thyroid function in NSTE-ACS patients after PCI. We observed that persistent SCH, which was defined by repeatedly monitoring serum TSH levels, was associated with more severe coronary artery lesions and had a higher risk of nonfatal myocardial infarction and unplanned PCI. Persistent SCH, which is independent of other recognized traditional risk factors, is an important predictor of MACCE in patients with NSTE-ACS treated with PCI.

Previous analyses based on observational studies used a single set of thyroid function tests to define SCH. However, a large number of patients with mild SCH can return to normal thyroid function.[14] In this study, patients were selected to be included in the SCH group only after four thyroid function tests within one month, which led to the exclusion of 46 patients with elevated TSH before PCI, who returned to normal thyroid function during postoperative follow-up. This group of patients accounted for 21.3% of all patients with elevated TSH levels. Up to 11% of patients with acute myocardial infarction and 17% of patients with NSTE-ACS can reportedly be diagnosed with SCH.[20,21] The higher incidence of SCH in this population may be related to the brief fluctuations in TSH levels during the acute period of acute myocardial infarction,[22] especially the brief increase in serum TSH levels within a few hours after onset.[8] This transient change in TSH levels may be related to iodinated contrast agents used in angiography. In our study, 35.3% of patients with SCH had normalisation of thyroid function among the 967 patients who completed the thyroid function test 6 months after PCI. This indicates the immense capacity of thyroid to overcome the iodide load. Most of the patients' TSH levels peaked from 1 day to 1 week after PCI, which was consistent with the findings of the latest study by Si et al.[23] They found that patients had a higher risk of transient hypothyroidism within 1 day and 1 month after using an iodized contrast agent, and the risk of subclinical thyroid dysfunction increased 1 and 6 months after surgery. Using a single set of thyroid function tests to define SCH may lead to more than 40% of elderly patients being misclassified[6] and may affect the results of longitudinal studies on the risk of health outcomes.

To some extent, this study was the first to establish the baseline rate of SCH and follow the trajectory of TSH values during and after hospitalisation for PCIs for up to 6 months. At present, it is not clear whether TSH can predict the severity of coronary artery lesions in patients with NSTE-ACS complicated with persistent SCH. Previous studies found that FT3 concentration in the normal range was negatively correlated with the Gensini score, while low FT3 concentration can independently predict coronary artery disease (CAD) and the severity of coronary artery lesions.[24] Bai et al.[25] also confirmed this conclusion and pointed out that patients with hypothyroidism and low T3 syndrome not only had a higher prevalence and severity of CAD, but also a poorer prognosis. However, there are other studies that drew the opposite conclusion that neither FT4 nor TSH was related to ln (Gensini score).[26] It is worth noting that Lee et al.[9] found that SCH was associated with re-PCI after in-stent restenosis, suggesting that SCH may aggravate coronary lesions by increasing stent intimal hyperplasia. We also observed that the severity of coronary artery lesions in patients with SCH was significantly higher than that in patients with ET. In addition, TSH levels significantly correlated with the degree of coronary artery lesions. Our results suggest that TSH may be an independent risk factor for the severity of coronary artery lesions in patients with NSTE-ACS complicated with SCH; however, a causal association could not be proven. A previous study showed that an increased concentration of TSH increases the degree of coronary artery lesions by aggravating vascular inflammation and atherosclerosis.[11] More studies are needed in the future to verify the causality and potential association mechanisms.

Although it has been confirmed that SCH is closely related to cardiac metabolism and the occurrence and development of hypercholesterolaemia and atherosclerosis, the potential relationship between SCH and MACCE remains controversial. The Thyroid Studies Collaboration found a significant increase in CHD-related mortality in patients with SCH, especially those with TSH ≥ 10.0 mIU/L. Similar observations were found in stroke, myocardial infarction, and heart failure events.[5,27,28] Izkhakov et al.[2] reported that SCH is closely related to short-term and long-term cardiovascular adverse events in STEMI patients undergoing PCI. A recent study by Moon reported an association between SCH and a greater risk of cardiovascular disease (CVD) and all-cause mortality in subpopulations with underlying CVD or high CVD risk.[4] At the same time, some researchers held the opposite view that patients with SCH did not show a higher risk of CVD and all-cause mortality than adults with normal thyroid function.[27,29] In elderly patients with SCH, neither transient nor persistent SCH can be used as a risk factor for CHD, heart failure or cardiac death.[14] In the present study, we evaluated a large cohort of NSTE-ACS patients treated with PCI and followed the risk of MACCE after PCI. Patients with persistent SCH had a higher risk of nonfatal MI and unplanned PCI. After adjusting for covariates, persistent SCH was still associated with a higher risk of MACCE in subgroups of different ages, genders, and moderate and severe coronary artery lesions. While there is an association, we currently do not have evidence that treating SCH in this setting will improve outcomes. A recent study did not support the treatment of SCH in patients with acute myocardial infarction.[30] However, thyroid hormone treatment may provide benefits in certain subgroups, such as patients who are younger or have more severe coronary artery lesions. There is a need for more prospective randomized studies on the impact of thyroxine treatment on outcomes in the future.

There are several potential mechanisms that explain the relationship between SCH and MACCE. In our study, the fasting blood glucose of SCH patients was significantly higher than that of ET patients, which was consistent with the findings of Xu et al.,[31] stating that SCH is associated with metabolic syndrome caused by increased insulin resistance. SCH can increase blood pressure by increasing systemic vascular resistance and cause endothelial dysfunction by reducing the availability of nitric oxide. The increase in TSH level is closely related to the increase in thrombus load, especially in NSTE-ACS complicated in SCH patients with both hypercoagulable and hypofibrinolytic states, which may lead to an increased risk of thrombosis.[32] The linear relationship between serum TSH and thrombus area in patients with NSTE-ACS suggests that there may be a causal relationship between elevated TSH levels and thrombus area. Although patients with NSTE-ACS and SCH received the best secondary prophylaxis, the thrombus load was still high.[21] This finding may explain the higher cardiovascular risk in patients with SCH in this study and support our results that SCH mediates the association of cardiovascular adverse events in patients with NSTE-ACS after PCI. Our results also suggest that SCH may not be an independent risk factor for nonfatal stroke after PCI. This may be because SCH has a neuroprotective effect on ischaemic stroke,[33] which can greatly reduce the probability of nonfatal stroke in the short term after PCI. To better explore the mechanism of ischaemic events such as myocardial infarction and stroke caused by persistent SCH, more pathogenesis-oriented studies are needed to explain the degree and type of coagulation and fibrinolytic abnormalities in patients with persistent SCH.