==== Front Eur J Med Res Eur J Med Res European Journal of Medical Research 0949-2321 2047-783X BioMed Central London 37381066 1149 10.1186/s40001-023-01149-9 Research Normal thyroid stimulating hormone is associated with all-cause mortality in patients with acute myocardial infarction after percutaneous coronary intervention Ni Wei-cheng 1 Kong Shu-ting 2 Lin Ken 1 Huang Yu-heng 1 Li Jun-feng 1 Shi San-ling 1 Lu Yu-cheng 1 Cheng Ling 1 Chen Chang-xi 1 Zhou Hao wyzh66@126.com 1 1 grid.414906.e 0000 0004 1808 0918 Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China 2 Department of Cardiology, Jin Hua Municipal Central Hospital, Jinhua, China 29 6 2023 29 6 2023 2023 28 19921 2 2023 29 5 2023 © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Background Circulating thyroid-stimulating hormone (TSH) levels within the normal reference range can affect the cardiovascular system. The present study investigated the prognostic value of normal TSH levels in patients presenting with acute myocardial infarction (AMI) following percutaneous coronary intervention (PCI). Methods Between January 2013 and July 2019, 1240 patients with AMI and normal thyroid function were enrolled and classified according to TSH tertile. The trial endpoint was all-cause mortality. The integrated discrimination index (IDI) and the net reclassification index (NRI) were used to assess the combined predictive values of the TSH levels and the Global Registry of Acute Coronary Events (GRACE) scores. Results After a median 44.25-month follow-up, 195 individuals died. Even after covariate adjustment by multivariate Cox regression (HR: 1.56; 95% CI 1.08–2.25; P = 0.017), the patients in the third TSH tertile were at the highest risk of all-cause mortality. A subgroup analysis revealed significant interactions between the TSH levels and the GRACE scores (high risk vs. low/medium risk) (P = 0.019). The addition of the TSH levels to the GRACE scores substantially improved the prediction of all-cause mortality, especially for high-risk patients (NRI = 0.239; IDI = 0.044; C-statistic value range 0.649–0.691; all significant). Conclusions The third TSH tertile is associated with a higher incidence of all-cause mortality than the first TSH tertile in high-risk patients presenting with AMI after PCI. Keywords Acute myocardial infarction Global Registry of Acute Coronary Events score Mortality Percutaneous coronary intervention Thyroid stimulating hormone The National Nature Science Foundation of China81873468 Zhou Hao issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2023 ==== Body pmcIntroduction There is a considerable risk of cardiovascular events in patients with acute myocardial infarction (AMI) despite substantial progress in percutaneous coronary intervention (PCI) and antithrombotic medication [1, 2]. Characterization of the factors contributing to this residual risk may reveal new strategies to mitigate it. Slight fluctuations in thyroid-stimulating hormone (TSH) levels significantly affect the cardiovascular system [3]. Patients with subclinical hypothyroidism or hyperthyroidism may be at a substantially higher risk of cardiovascular death and cardiac events than healthy individuals [4, 5]. Reference-range TSH levels are positively correlated with the development of hypothyroidism [6]. For these reasons, certain medical specialists have recommended lowering the upper TSH reference level [7]. High reference-range TSH levels are associated with hypertension [8], unhealthy body mass index (BMI), abnormal blood lipid metabolism [9], reduced glomerular filtration [10], recurrence of atrial tachyarrhythmia after catheter ablation of atrial fibrillation [11], cardiovascular disease (CVD), and all-cause mortality in patients with diabetes [12]. Prior research demonstrated that even within the reference range, the third TSH tertile is correlated with mortality in patients with coronary artery disease (CAD) who have undergone PCI [24]. To the best of our knowledge, few studies have investigated the prognostic value of normal TSH levels in patients with AMI [13]. The present study aimed to assess the value of reference-range TSH levels in the prognosis of all-cause mortality in a relatively large cohort of patients presenting with AMI who have undergone PCI. Methods Study population This retrospective observational cohort analysis consisted of 2348 patients who presented with AMI undergoing percutaneous coronary intervention (PCI) at the First Affiliated Hospital of Wenzhou Medical University between January 2013 and July 2019. Details of the recruitment process are shown in Fig. 1. The exclusion criteria were as follows: (1) missing thyroid function test (n = 562); (2) previous or current thyroid disease or current medication that could affect thyroid function, including thyroid hormone, antithyroid drugs, lithium, steroids, and amiodarone (n = 185); and (3) TSH levels beyond the 0.34–5.60 mIU/L reference range, or abnormal thyroid status (n = 361). A total of 1240 participants with normal thyroid function were enrolled in the present study, and the Ethics Review Board of the First Affiliated Hospital of Wenzhou Medical University approved the trial protocol.Fig. 1 Flow chart of the study Percutaneous coronary intervention (PCI) and medication The pre-PCI treatment consisted of aspirin, clopidogrel, or ticagrelor administration. Contraindications were excluded, patients received the glycoprotein IIb/IIIa inhibitor tirofiban and supplemental heparin, and dosages were based on body weight. The activated clotting time target range was 250–300 s during the procedure. After the PCI, aspirin, clopidogrel, or ticagrelor was administered as part of a standard 12-mo dual antiplatelet regimen. Beta-blockers, statins, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin II receptor blockers (ARBs) were administered according to recommended treatment protocols [1, 2]. Clinical laboratory data collection Clinical, laboratory, medication-at-discharge, and procedural baseline data were collected and the laboratory results were recorded at admission. Within 24 h of admission, patients fasted for > 8 h, and samples of their venous blood were collected and immediately analyzed in preparation for the thyroid function test and other routine biochemical measurements. The thyroid function test measured the TSH, triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), and free thyroxine (FT4) levels, and their reference ranges were 0.34–5.6 mIU/L, 1.34–2.73 nmol/L, 78.38–157.4 nmol/L, 3.28–6.47 pmol/L, and 7.64–16.03 pmol/L, respectively. Patients that were not being administered levothyroxine or antithyroid medications and had TSH, FT3, and FT4 within their respective reference ranges were considered to be euthyroid or have normal thyroid function. Outcomes and follow-up The target outcome was all-cause mortality. Every six months after the PCI, outcome data were collected using medical records, outpatient clinician visits, and telephone conversations. Statistical analysis Categorical variables were presented as frequencies and percentages. Continuous variables were reported as medians and interquartile ranges when the distributions were skewed. Means and standard deviations were reported when the distributions were normal. Continuous variables were compared using analysis of variance (ANOVA) or the Kruskal–Wallis test. Categorical variables were compared by Pearson’s χ2 or Fisher’s exact test. Kaplan–Meier curves were plotted to visualize temporal mortality distributions for patients in different TSH tertiles. All patient groups were compared by the log-rank test. Statistical adjustments accounted for age, sex, hypertension, diabetes, smoking history, hyperlipidemia, chronic kidney disease, previous coronary heart disease, Killip class, left ventricular ejection fraction (LVEF), GRACE score, three-vessel disease, and medications at discharge (beta-blockers, ACEI/ARB, and statins). Factors such as medications at discharge were extracted from Table 1 if they were clinically meaningful and strongly correlated with the risk of all-cause mortality. Parameters that significantly differed among the patients in various TSH tertiles were also considered. Variables such as age and sex linked to the TSH levels and the risk of adverse events were regarded as potential confounders. The final model was stabilized by removing highly collinear variables. The variables extracted from Table 1 were integrated into a forward-selected adjusted model. Covariates with variance inflation factor (VIF) ≥ 10 were removed from the final model. Hazard ratios (HR) were presented along with their corresponding 95% confidence intervals (CI).Table 1 Baseline patient characteristics Variables 1st tertile (n = 414) 2nd tertile (n = 416) 3rd tertile (n = 410) P-value Clinical characteristics  Age 65.23 ± 11.74 68 ± 12.32 70.31 ± 12.71  < 0.001  Male, n (%) 371 (89.61%) 332 (79.81%) 300 (73.17%)  < 0.001  Diabetes mellitus, n (%) 86 (20.77%) 77 (18.51%) 101 (24.63%) 0.094  Hypertension, n (%) 246 (59.42%) 235 (56.49%) 225 (54.88%) 0.41  Smoking history, n (%) 235 (56.76%) 232 (55.77%) 227 (55.37%) 0.917  Hyperlipidaemia, n (%) 277 (66.91%) 268 (64.42%) 254 (61.95%) 0.331  Chronic kidney disease, n (%) 34 (8.21%) 39 (9.38%) 70 (17.07%)  < 0.001  Previous coronary heart disease, n (%) 23 (5.56%) 14 (3.37%) 20 (4.88%) 0.304  Peripheral arterial disease, n (%) 78 (18.84%) 87 (20.91%) 81 (19.76%) 0.755  Killip class ≥ II, n (%) 72 (17.39%) 88 (21.15%) 97 (23.66%) 0.082  LVEF ≤ 40%, n (%) 66 (15.94%) 56 (13.46%) 65 (15.85%) 0.527 Diagnosis 0.059  STEMI 353 (85.27%) 361 (86.78%) 332 (80.98%)  NSTEMI 61 (14.73%) 55 (13.22%) 78 (19.02%)  GRACE scores, median (Q1, Q3) 112.5 (97,128) 117 (98,134) 121 (102,142)  < 0.001  High risk status 177 (42.75%) 203 (48.8%) 210 (51.22%) 0.043 Laboratory characteristics  White blood cells, median (Q1, Q3) 11.96 (9.81,14.38) 10.68 (8.84,13.31) 10.45 (8.62,13.33)  < 0.001  Haemoglobin (g/L), median (Q1, Q3) 136 (125.25,145) 133 (120.75,145) 129 (117,140)  < 0.001  Platelet (g/L), median (Q1, Q3) 213.5 (182,257) 212.5 (179,252) 210 (172,253) 0.458  Total cholesterol (mmol/L), median (Q1, Q3) 4.94 (4.31,5.66) 4.9 (4.22,5.74) 4.77 (4.08,5.59) 0.185  LDL-C (mmol/L), median (Q1, Q3) 3.13 (2.52,3.68) 3.1 (2.49,3.7) 2.96 (2.41,3.55) 0.112  Troponin(ng/ml), median (Q1, Q3) 16.47 (1,50) 13.71 (1.45,50) 11.58 (1.85,42.97) 0.586  CK-MB(U/L), median (Q1, Q3) 284.5 (151,503) 245 (130,437.5) 194 (91,397.75)  < 0.001  Creatinine(mg/dL), median (Q1, Q3) 67 (58.25,80) 68.5 (58,81.25) 69 (57,87) 0.438  Lactate(mmol/L), median (Q1, Q3) 2.7 (2.1,3.7) 2.7 (2.08,3.62) 2.8 (2.2,3.8) 0.094  TSH(mIU/L), median (Q1, Q3) 0.53 (0.45,0.62) 0.92 (0.8,1.05) 1.83 (1.47,2.5)  < 0.001  Triiodothyronine(nmol/L), median (Q1, Q3) 1.1 (0.93,1.32) 1.12 (0.95,1.32) 1.16 (0.97,1.33) 0.066  Thyroxine(nmol/L), median (Q1, Q3) 99.13 (86.45,114.52) 99.57 (85.23,113.88) 100.1 (86.86,114.64) 0.602  Free triiodothyronine (pmol/L), median (Q1, Q3) 4.2 (3.8,4.7) 4.24 (3.9,4.8) 4.3 (3.9,4.7) 0.543  Free thyroxine(pmol/L), median (Q1, Q3) 10.98 (9.81,12.52) 10.95 (9.86,12.5) 11.23 (9.99,12.7) 0.232 Medications at discharge  Aspirin, n (%) 413 (99.76%) 416 (100%) 409 (99.76%) 0.554  Clopidogrel, n (%) 412 (99.52%) 415 (99.76%) 409 (99.76%) 0.78  Beta-Blockers, n (%) 347 (83.82%) 341 (81.97%) 306 (74.63%) 0.002  ACEI/ARBs, n (%) 251 (60.63%) 267 (64.18%) 236 (57.56%) 0.149  Statins, n (%) 402 (97.1%) 410 (98.56%) 396 (96.59%) 0.179 Procedural characteristics  LM stenosis ≥ 50, n (%) 9 (2.17%) 14 (3.37%) 14 (3.41%) 0.494  LAD stenosis ≥ 50, n (%) 324 (78.26%) 339 (81.49%) 315 (76.83%) 0.243  LCA stenosis ≥ 50, n (%) 174 (42.03%) 190 (45.67%) 177 (43.17%) 0.556  RCA stenosis ≥ 50, n (%) 218 (52.66%) 220 (52.88%) 231 (56.34%) 0.493  Three-vessel disease, n (%) 94 (22.71%) 110 (26.44%) 116 (28.29%) 0.175  Calcification, n (%) 28 (6.76%) 41 (9.86%) 39 (9.51%) 0.224  Thrombus, n (%) 189 (45.65%) 177 (42.55%) 156 (38.05%) 0.085 STEMI, ST-segment elevation myocardial infarction; NSTEMI, Non-ST-segment elevation myocardial infarction; GRACE, Global Registry of Acute Coronary Events; LVEF, left ventricular ejection fraction; LDL-C, low-density lipoprotein cholesterol level; CK-MB-creatine kinase isoenzymes; TSH, thyroid stimulating hormone; ACEI/ARB, angiotensin converting enzyme inhibitor/angiotensin receptor blocker; LM- left main disease; LAD, left anterior descending coronary; LCX, left circumflex artery; RCA, right coronary artery A restricted cubic spline analysis including the 25th, 50th, and 75th percentiles was performed on the nonlinear association between the TSH concentration and the all-cause mortality within the first and 95th percentiles to minimize the influence of potential outliers. The 25th percentile was the reference, and nonlinearity was identified by the likelihood ratio test. The TSH level was combined with the GRACE score to evaluate the discrimination and reclassification performance of TSH. The GRACE score has been extensively used to predict mortality in patients with AMI [14]. The C-statistic, continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were also calculated. Statistical significance was defined as two-tailed P < 0.05. R v. 4.0.3 (R Core Team, Vienna, Austria) and SPSS v. 25.0 (IBM Corp., Armonk, NY, USA) were used for all statistical analyses. Results Baseline characteristics Out of the 2348 consecutive patients presenting with AMI and undergoing emergency PCI during the study period, 1108 were excluded (Fig. 1). The remaining 1,240 patients had a mean age of 67.8 ± 12.4 yrs and 80.9% of them were male. Of these, 706 (56.9%) had hypertension, 264 (21.3%) were previously diagnosed with diabetes, and 799 (64.4%) had hyperlipidemia. Table 1 lists the baseline clinical, laboratory, medication, and procedural data of the study groups. The patients in the third TSH tertile were significantly older and there were fewer males than those in the other two groups. The prevalence of chronic kidney disease and the number of high-risk patients (according to the GRACE score) were significantly higher in the third TSH tertile than in the other two groups. The white blood cell (WBC) counts, the hemoglobin and creatine kinase isoenzyme (CK-MB) levels, and the rates of beta-blocker consumption were significantly lower in the patients of the third TSH tertile than they were in those of the other two groups. Association between TSH level and all-cause mortality The median and interquartile ranges of the follow-up times were 44.25 mo and 30.64–67.23 mo, respectively. All-cause mortality occurred in 195 (15.7%) patients. There were 49 (11.8%), 56 (13.4%), and 90 (21.9%) deaths in the first, second, and third TSH tertile, respectively. The Kaplan–Meier plot demonstrated that all-cause death at follow-up was significantly higher for the patients in the third tertile than it was for those in the first and second tertile (log-rank test P < 0.001; Fig. 2).Fig. 2 Kaplan–Meier analysis for all-cause mortality according to tertiles of TSH level The univariate analysis in Table 2 shows that the patients in the third TSH tertile were at a higher relative risk of all-cause mortality (HR = 2.01; 95% CI 1.42–2.85) than those in the first but not those in the second TSH tertile (HR: 1.19; 95% CI 0.81–1.74). Covariate adjustment by multivariate Cox regression disclosed that the association between the third TSH tertile and all-cause mortality lasted longer (HR: 1.56; 95% CI 1.08–2.25; P = 0.017) than that between the first TSH tertile and all-cause mortality. Age > 65 yrs, diabetes mellitus, chronic kidney disease, Killip class ≥ II, LVEF ≤ 40%, ACEI/ARB administration at discharge, three-vessel disease, and high-risk status were independently associated with all-cause death.Table 2 Results of univariate and multivariate Cox proportional hazards model applied to assess predictors of all-cause mortality Variables Univariate analysis HR[95%CI] P-value Multivariate analysis HR[95%CI] P-value TSH, categorical  1st Ref. – Ref. –  2nd 1.19[0.81,1.74] 0.384 1.11[0.75,1.65] 0.605  3rd 2.01[1.42,2.85]  < 0.001 1.56[1.08,2.25] 0.017  Age > 65 years 3.64[2.46,5.37]  < 0.001 1.87[1.15,3.02] 0.011  Male 0.59[0.43,0.8] 0.001 1.04[0.72,1.50] 0.822  Hypertension 1.53[1.14,2.06] 0.005 1.21[0.87,1.67] 0.259  Diabetes mellitus 1.76[1.3,2.38]  < 0.001 1.51[1.09,2.10] 0.013  Smoking history 1.01[0.76,1.35] 0.918 1.23[0.91,1.66] 0.178  Hyperlipidaemia 0.85[0.64,1.14] 0.278 0.93[0.69,1.25] 0.638  Chronic kidney disease 4.86[3.59,6.58]  < 0.001 2.09[1.46,2.98]  < 0.001  Previous coronary heart disease 2.01[1.22,3.31] 0.006 1.10[0.65,1.85] 0.718  Killip class ≥ II 3.39[2.55,4.5]  < 0.001 2.05[1.50,2.82]  < 0.001  LVEF ≤ 40% 3.07[2.27,4.14]  < 0.001 2.28[1.67,3.12]  < 0.001  Beta-Blockers 0.56[0.42,0.77]  < 0.001 0.88[0.63,1.22] 0.443  ACEI/ARBs 0.46[0.35,0.61]  < 0.001 0.52[0.38,0.70]  < 0.001  Statins 0.66[0.31,1.41]  < 0.001 0.99[0.45,2.18] 0.981  Three-vessel disease 1.91[1.43,2.55]  < 0.001 1.47[1.09,2.00] 0.012  High risk status 3.36[2.45,4.62]  < 0.001 1.52[1.02,2.26] 0.04 TSH, thyroid stimulating hormone; LVEF, left ventricular ejection fraction; ACEI/ARB, angiotensin converting enzyme inhibitor/angiotensin receptor blocker; HR, hazard ratio; CI, confidence interval The restricted cubic spline in Fig. 3 depicts the association between the TSH level and all-cause mortality after covariate adjustment by multivariate Cox regression. TSH levels > 0.92 mIU/mL were positively and linearly correlated with an increased risk of all-cause mortality (Pnonlinearity = 0.923).Fig. 3 Restricted cubic splines of TSH concentration for hazard ratios of all-cause mortality in AMI patients. Red lines represent the hazard ratio, black dashed lines represent the 95% confidence intervals Subgroup analysis Interactions among age, sex, diabetes, hypertension, clinical presentation, and GRACE score strata were evaluated after covariate adjustment by multivariate Cox regression. Strata variables were not included when they were stratified alone. Table 3 shows that the patients in the third TSH tertile were at higher risk of all-cause mortality than those in the first TSH tertile and at all strata analyzed except females, younger patients, and those with diabetes, non-ST-segment elevation myocardial infarction (NSTEMI), low/medium risk status, and no hypertension.Table 3 Subgroup analysis on all-cause mortality across tertiles of TSH levels TSH tertiles No. of patients with events (%) Adjusted HR [95% CI] P for interaction 1st tertile 2nd tertile 3rd tertile 1st tertile 2nd tertile 3rd tertile Total 49(11.8) 56(13.4) 90(21.9) Ref. 1.11[0.75,1.65] 1.56[1.08,2.25] Age 0.34   > 65 years 38(17.1) 50(19.3) 77(28.3) Ref. 1.18[0.76,1.83] 1.53[1,02,2.30]   ≤ 65 years 11(5.7) 6(3.7) 13(9.4) Ref. 0.62[0.21,1.83] 1.40[0.53,3.70] Sex 0.555  Male 39(10.5) 43(12.9) 59(19.6) Ref. 1.24[0.80,1.94] 1.59[1.04,2.43]  Female 10(23.2) 13(15.4) 31(28.1) Ref. 0.68[0.27,1.68] 1.08[0.49,2.4] Diabetes 0.944  Yes 15(17.4) 15(19.4) 30(29.7) Ref. 0.97[0.44,2.13] 1.23[0.6,2.55]  No 34(10.3) 41(12.0) 60(19.4) Ref. 1.29[0.81,2.07] 1.73[1.11,2.69] Hypertension 0.729  Yes 31(12.6) 39(16.5) 59(26.2) Ref. 1.39[0.85,2.26] 1.82[1.15,2.87]  No 18(10.7) 17(9.3) 31(16.7) Ref. 0.62[0.32,1.24] 0.97[0.52,1.82] Clinical presentation 0.380  STEMI 41(11.6) 45(12.4) 76(22.8) Ref. 1.06[0.69,1.64] 1.76[1.18,2.63]  NSTEMI 8(13.1) 11(20.0) 14(17.9) Ref. 1.41[0.51,3.93] 1.65[0.70,3.89] GRACE score 0.019  High risk 30(16.9) 38(18.7) 75(35.7) Ref. 1.27[0.77,2.01] 2.02[1.29,3.16]  Low/medium risk 19(8.0) 18(8.4) 15(7.5) Ref. 0.93[0.47,1.83] 0.69[0.33,1.45] GRACE score- Global Registry of Acute Coronary Events score; TSH- thyroid stimulating hormone; HR- hazard ratio; CI- confidence interval For all-cause mortality, there was a significant interaction between the GRACE score (high risk or low/medium risk) and the TSH level (Pinteraction = 0.019). For the subgroup with high-risk status, the HR for all-cause mortality was 2.02 (95% CI 1.29–3.16) in the third TSH tertile relative to the first TSH tertile (reference) group. For the subgroup with low/medium-risk status, the HR for all-cause mortality was 0.69 (95% CI 0.33–1.45) in the third TSH tertile relative to the first TSH tertile (reference) group. There were no significant interactions between the TSH and any other strata variable associated with the risk of all-cause mortality. Prognostic value of combining the TSH with the GRACE score The prognostic value of combining the TSH with the GRACE score to predict all-cause mortality in patients with AMI is shown in Table 4. Compared with the baseline GRACE score model, the addition of TSH significantly improved reclassification based on the NRI (0.172; 95% CI 0.057–0.265; P < 0.001), IDI (0.024; 95% CI 0.009–0.054; P < 0.001), and C-statistic (0.732–0.742; P < 0.001). For the high-risk group, the addition of the TSH to the GRACE score significantly improved reclassification based on the NRI (23.9% improvement; 0.239; 95% CI 0.097–0.339; P = 0.007) and IDI (4.4% improvement; 0.044; 95% CI 0.014–0.093; P < 0.001) and significantly increased the C-statistic from 0.649 (95% CI 0.601–0.697) to 0.691 (95% CI 0.644–0.737) (P < 0.001). For the low/medium-risk group, however, there were no statistically significant incremental effects with respect to the C-statistic (0.710–0.711; P = 0.607), NRI (3.7% improvement; P = 0.492), or IDI (0.1% improvement; P = 0.555).Table 4 Evaluation of the predictive value of TSH combined with GRACE score for all-cause mortality NRI IDI C-Statistic Index(95% CI) P-value Index(95% CI) P-value Index(95% CI) P-value Total population  GRACE score – Ref. – Ref. 0.732(0.696,0.767) Ref.  GRACE score + TSH 0.172(0.057,0.265)  < 0.001 0.024(0.009,0.054)  < 0.001 0.742(0.706,0.779)  < 0.001 High risk group  GRACE score – Ref. – Ref. 0.649(0.601,0.697) Ref.  GRACE score + TSH 0.239(0.097,0.339) 0.007 0.044(0.014,0.093)  < 0.001 0.691(0.644,0.737)  < 0.001 Low / medium risk group  GRACE score – Ref. – Ref. 0.710(0.641,0.779) Ref.  GRACE score + TSH 0.037(− 0.082,0.173) 0.492 0.001(− 0.001,0.031) 0.555 0.711(0.642,0.781) 0.607 GRACE score- Global Registry of Acute Coronary Events score; TSH- thyroid stimulating hormone; NRI- net-reclassification index; IDI- integrated discrimination improvement; CI- confidence interval Discussion The present study indicated that within its reference range, the third TSH tertile was independently associated with the risk of all-cause mortality in patients presenting with AMI after PCI. Moreover, a subgroup analysis revealed an interaction between the TSH level and the GRACE score. Hence, a high normal TSH level had prognostic value for patients at high (but not low/medium) risk of all-cause mortality. The present work also showed that the addition of the TSH improved the ability of the GRACE score to predict patients with AMI who are at high risk of all-cause mortality. The pathophysiological mechanisms linking TSH levels in the upper part of the reference range to an elevated risk of all-cause mortality are not clear. TSH caused extrathyroidal effects such as in vitro interleukin-6 (IL-6) induction and tumor necrosis factor (TNF) biosynthesis [15, 16] as well as in vivo upregulation of nitric oxide (NO) metabolites [17]. Earlier studies proposed that elevated TSH increases the risk of all-cause mortality in patients with AMI by increasing mitochondrial oxidative stress, the proinflammatory state, thrombogenicity, and endothelial dysfunction, and by decreasing heart function [15, 17–20]. Here, the TSH level and all-cause mortality were strongly positively correlated even after adjusting for age, sex, and other potential confounders. Hence, the pathophysiological mechanisms by which the TSH level predicts all-cause death in patients with AMI remain to be elucidated. TSH levels in the upper limit of the normal range indicate the early stages of hypothyroidism [6]. This condition is associated with mortality and cardiovascular events in various cardiovascular diseases (CVDs) and different symptoms in the general population [21, 22]. In a population-based study, a mediation analysis associated a high risk of all-cause mortality with CVD. Patients with high normal TSH were at greater risk of all-cause death and CVD than those with mid- to normal TSH [22]. High normal TSH was also associated with an increased risk of ventricular arrhythmia in patients with dilated cardiomyopathy. Thus, it is essential to monitor TSH levels [23]. A Ndrepepa trial on 8010 post-PCI patients revealed that third-tertile TSH within the reference range was associated with an elevated risk of all-cause death within the first 30 days of PCI but not between 30 days and three years after it [24]. However, a meta-analysis disclosed no correlations between normal-range TSH levels and the risks of coronary heart disease events and mortality [25]. To the best of our knowledge, only a few studies have focused on normal TSH levels in patients with AMI. A small-sample study conducted in Turkey demonstrated that patients in the high TSH tertile with acute coronary heart disease were at a higher risk of short-term all-cause death than those in the low- to mid-TSH tertile [13]. Observational research on a cohort of 1203 patients with ST-segment elevation myocardial infarction (STEMI) demonstrated a correlation between normal TSH levels and mortality in patients who did not undergo emergency reperfusion therapy. However, the foregoing parameters were not correlated in STEMI patients who were administered this treatment [26]. Nevertheless, a study on 1186 individuals showed that normal high TSH values did not affect the prognosis of patients with STEMI [27]. The results of the preceding studies were inconsistent as they did not control for low T3 syndrome or other types of abnormal thyroid function status. Low T3 syndrome is associated with poor prognosis in patients with heart disease and may, therefore, influence the relationship between the TSH level and mortality [28]. To the best of our knowledge, the present work is the first to demonstrate an association between high TSH levels within the reference range and long-term all-cause mortality in patients presenting with AMI following PCI. This study also confirmed that the TSH can enhance the ability of the GRACE score to predict all-cause mortality accurately. The GRACE score has been extensively used in clinical settings to determine the prognosis of patients with AMI [14, 31, 35]. Our subgroup analysis revealed significant interactions between normal TSH levels and the GRACE score (high- or low/medium-risk status). The risk of all-cause mortality was similar across all TSH levels in patients with low/medium-risk status. High normal TSH levels were associated with an elevated risk of all-cause mortality in patients with high-risk status. The addition of the TSH significantly enhanced the prognostic value of the GRACE score by comparing the C-statistics, IDI, and NRI, thereby improving the prediction of the risk of all-cause mortality in patients with high-risk (but not low/medium-risk) status. Mortality related to high normal TSH levels was relatively greater in high-risk than low/medium-risk patients. Dysregulated basal metabolism and slightly abnormal peripheral thyroid hormone metabolism are often associated with poor prognosis in critically ill patients [29, 30]. We hypothesized that high normal TSH levels in patients with elevated GRACE scores might indicate aberrant thyroid metabolism and, therefore, a relatively high risk of all-cause mortality. There is a lack of consensus as to whether thyroid hormone replacement therapy should be administered to patients with AMI. A study in Greece showed that acute triiodothyronine treatment improved postischemic cardiac function in patients with MI [32]. Another investigation reported that levothyroxine treatment did not improve left ventricular function in patients with AMI and subclinical hypothyroidism [33]. Relative to untreated controls, levothyroxine therapy nonsignificantly (Pinteraction = 0.44) improved baseline reduced LVEF in certain patients. Low LVEF and high prognostic scores reflect high disease severity and adverse events in patients with AMI [14, 34–36]. Thus, thyroid hormone replacement therapy might be beneficial for patients with high GRACE scores. Future research in this area should be conducted on large cohorts. Prior studies reported conflicting optima for TSH reference ranges [37, 38]. Serum TSH levels indicate thyroid-pituitary feedback, but may not reliably reflect thyroid function in all organs [39]. Therefore, adverse cardiovascular effects could occur even at TSH levels that lie within the reference range. The TSH reference range must, therefore, be re-evaluated for each type of condition as well as AMI. Limitations The present study had several limitations. First, the TSH levels were only calculated at baseline. Hence, dynamic changes that might have occurred during follow-up were overlooked. Second, the present investigation was a single-center observational study. Therefore, potential confounders might not have been fully adjusted. Third, thyroid autoantibodies were not measured. They should have been considered as they might explain the pathophysiological mechanism by which high normal TSH levels are associated with the risk of all-cause mortality in patients presenting with AMI after PCI. Conclusion High TSH levels within the reference range were independently associated with a high risk of all-cause mortality in patients presenting with AMI following PCI. The addition of TSH improves the prognostic value of the GRACE score in the stratification of the risk of all-cause mortality in the aforementioned patients. Abbreviations ACEI Angiotensin-converting enzyme inhibitor AMI Acute myocardial infarction ARB Angiotensin II receptor blocker CAD Coronary artery disease CI Confidence interval CK-MB Creatine kinase isoenzymes FT3 Free triiodothyronine FT4 Free thyroxine GRACE Global Registry of Acute Coronary Events HR Hazard ratio IDI Integrated discrimination improvement IL-6 Interleukin-6 LAD Left anterior descending coronary LCX Left circumflex artery LM Left main disease LVEF Left ventricular ejection fraction NRI Net reclassification improvement NSTEMI Non-ST-segment elevation myocardial infarction PCI Percutaneous coronary intervention RCA Right coronary artery STEMI ST-segment elevation myocardial infarction T3 Triiodothyronine T4 Thyroxine TNF Tumor necrosis factor TSH Thyroid stimulating hormone VIF Variance inflation factor Acknowledgements The authors thank the patients of the First Affiliated Hospital of Wenzhou Medical University who were enrolled in the present trial. We also thank Bullet Edits Limited for language editing and manuscript proofreading. Author contributions WCN and HZ contributed to the trial conception and design. WCN, STK, LK, JFL, YHH, YCL, SLS, and LC contributed to the data collection and analysis. WCN drafted the manuscript. CXC and HZ critically revised the manuscript. All authors read and approved the final manuscript. Funding This work was financially supported by The National Nature Science Foundation of China (No. 81873468; http://www.nsfc.gov.cn). Availability of data and materials The data supporting this article will be made available by the authors upon reasonable written request. Declarations Ethics approval and consent to participate The First Affiliated Hospital of the Ethics Committee in Clinical Research of Wenzhou Medical University examined and approved the present research involving human subjects. The participants provided written informed consent before being enrolled in this trial. Any identifying photographs or data included in this manuscript were published with the consent of the informed individuals. Consent for publication Not applicable. Competing interests The authors of the present study attest that there were no financial or commercial ties that might be construed as potential competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References 1. Levine GN Bates ER Blankenship JC 2015 ACC/AHA/SCAI focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American college of cardiology/American heart association task force on clinical practice guidelines and the society for cardiovascular angiography and interventions Circulation 2016 133 11 1135 1147 10.1161/CIR.0000000000000336 26490017 2. Silber S Albertsson P Avilés FF Guidelines for percutaneous coronary interventions. The task force for percutaneous coronary interventions of the European society of cardiology Eur Heart J 2005 26 8 804 847 10.1093/eurheartj/ehi138 15769784 3. Müller P Leow MK Dietrich JW Minor perturbations of thyroid homeostasis and major cardiovascular endpoints-Physiological mechanisms and clinical evidence Front Cardiovasc Med 2022 9 942971 10.3389/fcvm.2022.942971 36046184 4. Manolis AA Manolis TA Melita H Manolis AS Subclinical thyroid dysfunction and cardiovascular consequences: an alarming wake-up call? Trends Cardiovasc Med 2020 30 2 57 69 10.1016/j.tcm.2019.02.011 30871865 5. Chaker L Razvi S Bensenor IM Azizi F Pearce EN Peeters RP Hypothyroidism correction appears in Nat Rev Dis Primers Nat Rev Dis Primers 2022 8 1 30 10.1038/s41572-022-00357-7 35589725 6. Åsvold BO Vatten LJ Midthjell K Bjøro T Serum TSH within the reference range as a predictor of future hypothyroidism and hyperthyroidism: 11-year follow-up of the HUNT Study in Norway J Clin Endocrinol Metab 2012 97 1 93 99 10.1210/jc.2011-1724 22049180 7. Wartofsky L Dickey RA The evidence for a narrower thyrotropin reference range is compelling J Clin Endocrinol Metab 2005 90 9 5483 5488 10.1210/jc.2005-0455 16148345 8. Kuś A Marouli E Del Greco MF Variation in normal range thyroid function affects serum cholesterol levels, blood pressure, and type 2 diabetes risk: a Mendelian randomization study Thyroid 2021 31 5 721 731 10.1089/thy.2020.0393 32746749 9. Ren R Ma Y Deng F Association between serum TSH levels and metabolic components in euthyroid subjects: a nationwide population-based study Diabetes Metab Syndr Obes 2019 12 1563 1569 10.2147/DMSO.S202769 31686877 10. Asvold BO Bjøro T Vatten LJ Association of thyroid function with estimated glomerular filtration rate in a population-based study: the HUNT study Eur J Endocrinol 2011 164 1 101 105 10.1530/EJE-10-0705 20930062 11. Morishima I Okumura K Morita Y High-normal thyroid-stimulating hormone shows a potential causal association with arrhythmia recurrence after catheter ablation of atrial fibrillation J Am Heart Assoc 2018 7 14 e009158 10.1161/JAHA.118.009158 30005553 12. Zhu P Lao G Chen C Luo L Gu J Ran J TSH levels within the normal range and risk of cardiovascular and all-cause mortality among individuals with diabetes Cardiovasc Diabetol 2022 21 1 254 10.1186/s12933-022-01698-z 36419168 13. Gürdoğan M Altay S Korkmaz S The effect of thyroid stimulating hormone level within the reference range on in-hospital and short-term prognosis in acute coronary syndrome patients Medicina (Kaunas) 2019 55 5 175 10.3390/medicina55050175 31137601 14. Fox KA Dabbous OH Goldberg RJ Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE) BMJ 2006 333 7578 1091 10.1136/bmj.38985.646481.55 17032691 15. Antunes TT Gagnon A Bell A Sorisky A Thyroid-stimulating hormone stimulates interleukin-6 release from 3T3-L1 adipocytes through a cAMP-protein kinase A pathway Obes Res 2005 13 12 2066 2071 10.1038/oby.2005.256 16421339 16. Wang HC Dragoo J Zhou Q Klein JR An intrinsic thyrotropin-mediated pathway of TNF-alpha production by bone marrow cells Blood 2003 101 1 119 123 10.1182/blood-2002-02-0544 12393601 17. Giusti M Valenti S Guazzini B Circulating nitric oxide is modulated by recombinant human TSH administration during monitoring of thyroid cancer remnant J Endocrinol Invest 2003 26 12 1192 1197 10.1007/BF03349156 15055471 18. Kahaly GJ Cardiovascular and atherogenic aspects of subclinical hypothyroidism Thyroid 2000 10 8 665 679 10.1089/10507250050137743 11014311 19. Viswanathan G Balasubramaniam K Hardy R Marshall S Zaman A Razvi S Blood thrombogenicity is independently associated with serum TSH levels in post-non-ST elevation acute coronary syndrome J Clin Endocrinol Metab 2014 99 6 E1050 E1054 10.1210/jc.2013-3062 24628547 20. Huang W Xu J Jing F Functional thyrotropin receptor expression in the ventricle and the effects on ventricular BNP secretion Endocrine 2014 46 2 328 339 10.1007/s12020-013-0052-6 24065308 21. Asvold BO Bjøro T Platou C Vatten LJ Thyroid function and the risk of coronary heart disease: 12-year follow-up of the HUNT study in Norway Clin Endocrinol (Oxf) 2012 77 6 911 917 10.1111/j.1365-2265.2012.04477.x 22724581 22. Inoue K Ritz B Brent GA Ebrahimi R Rhee CM Leung AM Association of subclinical hypothyroidism and cardiovascular disease with mortality JAMA Netw Open 2020 3 2 e1920745 10.1001/jamanetworkopen.2019.20745 32031647 23. Li X Yao Y Chen Z Thyroid-stimulating hormone within the normal range and risk of major adverse cardiovascular events in nonischemic dilated cardiomyopathy patients with severe left ventricular dysfunction Clin Cardiol 2019 42 1 120 128 10.1002/clc.23117 30447088 24. Ndrepepa G Braun S Mayer K Prognostic value of thyroid-stimulating hormone within reference range in patients with coronary artery disease Metabolism 2015 64 10 1308 1315 10.1016/j.metabol.2015.07.009 26298467 25. Åsvold BO Vatten LJ Bjøro T Thyroid function within the normal range and risk of coronary heart disease: an individual participant data analysis of 14 cohorts JAMA Intern Med 2015 175 6 1037 1047 10.1001/jamainternmed.2015.0930 25893284 26. Sun L Xiao K Miao Z Prognostic value of normal thyroid stimulating hormone in long-term mortality in patients with STEMI Front Endocrinol (Lausanne) 2022 13 806997 10.3389/fendo.2022.806997 35273563 27. Zhu Y Shen J Xue Y The association between thyroid-stimulating hormone and long-term outcomes in patients with ST segment elevation myocardial infarction treated by primary percutaneous coronary intervention Int J Gen Med 2021 14 6295 6303 10.2147/IJGM.S333322 34629894 28. Iervasi G Pingitore A Landi P Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease Circulation 2003 107 5 708 713 10.1161/01.cir.0000048124.64204.3f 12578873 29. Fliers E Bianco AC Langouche L Boelen A Thyroid function in critically ill patients Lancet Diabetes Endocrinol 2015 3 10 816 825 10.1016/S2213-8587(15)00225-9 26071885 30. Fliers E Alkemade A Wiersinga WM The hypothalamic-pituitary-thyroid axis in critical illness Best Pract Res Clin Endocrinol Metab 2001 15 4 453 464 10.1053/beem.2001.0163 11800517 31. Rencuzogullari I Çağdaş M Karabağ Y Value of syntax score II for predicting in-hospital and long-term survival in octogenarians with ST-segment elevation myocardial infarction: a comparison of six different risk scores Arch Gerontol Geriatr 2019 83 37 43 10.1016/j.archger.2019.03.016 30939363 32. Pantos CI Trikas AG Pissimisis EG Effects of acute triiodothyronine treatment in patients with anterior myocardial infarction undergoing primary angioplasty: evidence from a pilot randomized clinical trial (ThyRepair Study) Thyroid 2022 32 6 714 724 10.1089/thy.2021.0596 35297659 33. Jabbar A Ingoe L Junejo S Effect of levothyroxine on left ventricular ejection fraction in patients with subclinical hypothyroidism and acute myocardial infarction: a randomized clinical trial JAMA 2020 324 3 249 258 10.1001/jama.2020.9389 32692386 34. Yildiz I Rencüzoğulları I Karabağ Y Karakayali M Artac I Gurevin MS Predictors of left ventricular ejection function decline in young patients with ST-segment elevation myocardial infarction Rev Assoc Med Bras 2022 68 6 802 807 10.1590/1806-9282.20220033 35766695 35. Ozbeyaz NB Gokalp G Algul E H2FPEF score and contrast-induced nephropathy in patients with acute coronary syndrome undergoing percutaneous coronary intervention Angiology 2023 74 2 181 188 10.1177/00033197221099425 35503102 36. Algül E Özbeyaz NB Şahan HF Aydınyılmaz F Sunman H Tulmaç M Stress hyperglycemia ratio is associated with high thrombus burden in patients with acute coronary syndrome Angiology 2023 10.1177/00033197231167054 37005730 37. Larisch R Giacobino A Eckl W Wahl HG Midgley JE Hoermann R Reference range for thyrotropin Post hoc assessment Nuklearmedizin 2015 54 3 112 117 10.3413/Nukmed-0671-14-06 25567792 38. Razvi S Bhana S Mrabeti S Challenges in interpreting thyroid stimulating hormone results in the diagnosis of thyroid dysfunction J Thyroid Res 2019 2019 4106816 10.1155/2019/4106816 31662841 39. Escobar-Morreale HF Botella-Carretero JI Escobar del Rey F Morreale de Escobar G REVIEW: treatment of hypothyroidism with combinations of levothyroxine plus liothyronine J Clin Endocrinol Metab 2005 90 8 4946 4954 10.1210/jc.2005-0184 15928247