https://orcid.org/0000-0003-1010-9803
Figures
Abstract
Background
Recent studies have indicated that the triglyceride-glucose (TyG) index or subclinical thyroid dysfunction is associated with carotid plaques, a predictor of cardiovascular disease risk. However, evidence for this association is limited and inconsistent. This study aimed to evaluate the risk of carotid plaques according to TyG index and thyroid function status in the general population.
Methods
A total of 2,931 individuals who underwent carotid ultrasound as part of a comprehensive health examination at the Health Promotion Center of Soonchunhyang University Hospital were retrospectively reviewed. Based on the TyG index and thyroid function status, the participants were divided into six groups: LoTyG-SHyper (low TyG index with subclinical hyperthyroidism), LoTyG-Eu (low TyG index with euthyroidism), LoTyG-SHypo (low TyG index with subclinical hypothyroidism), HiTyG-SHyper (high TyG index with subclinical hyperthyroidism), HiTyG-Eu (high TyG index with euthyroidism), and HiTyG-SHypo (high TyG index with subclinical hypothyroidism). A multivariate logistic regression analysis was conducted to determine the risk of carotid plaques.
Results
The proportion of participants with significant carotid plaques was significantly different among the six groups (p<0.001, p for trend<0.001). The odds ratio (OR) and 95% confidence interval (CI) for significant carotid plaques were significantly higher in the HiTyG-SHypo group than in the LoTyG-Eu group, even after adjusting for confounding variables including sex, age, smoking, obesity, hypertension and diabetes mellitus (OR 1.506, 95% CI 1.045–2.170, p = 0.028). The OR of significant carotid plaques was higher in the HiTyG-Eu group than in the LoTyG-Eu group; however no associations were observed after additional adjustment for confounding variables.
Citation: Kim HJ, Kwon SS, Park SJ, Byun DW, Suh K, Yoo MH, et al. (2022) Risk of carotid plaques according to triglyceride-glucose index stratified by thyroid function: A cross-sectional study. PLoS ONE 17(12): e0279494. https://doi.org/10.1371/journal.pone.0279494
Editor: Gulali Aktas, Bolu Abant İzzet Baysal University: Bolu Abant Izzet Baysal Universitesi, TURKEY
Received: September 22, 2022; Accepted: December 8, 2022; Published: December 30, 2022
Copyright: © 2022 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This study was supported by Soonchunhyang University Research Fund to Dr. Hye Jeong Kim.
Competing interests: The authors have no competing interests to disclose.
Introduction
Carotid artery plaques have been studied as a surrogate marker of cardiovascular diseases (CVD), further stratifying at-risk individuals to help identify those most likely to benefit from aggressive medical therapy and lifestyle modifications [1–3]. Recent studies suggest that quantitative carotid plaque scores may be the best carotid ultrasound predictors of CVD risk [4, 5].
Insulin resistance is an independent risk factor for CVD [6]. The triglyceride-glucose (TyG) index is regarded as a valuable biomarker of insulin resistance [7]. Recently, several studies have reported that the TyG index is associated with carotid plaques in the general population [8–13].
Thyroid hormones are involved in energy homeostasis [14], lipid and glucose metabolism [15–17], and blood pressure (BP) [18]. Thyroid dysfunction is associated with an increased risk of CVD [19, 20]. Data on the role of subclinical thyroid dysfunction in the development of atherosclerosis are still inconclusive. Although some studies have found no association between subclinical thyroid dysfunction and carotid plaques [21, 22], other studies have identified subclinical thyroid dysfunction as a risk factor for carotid plaques [23, 24]. Previous studies have shown an association between thyroid function and insulin resistance measured using the TyG index [25, 26]. To the best of our knowledge, to date, no studies have addressed the differences in the risk of carotid plaques according to the TyG index and thyroid function status.
In the present study we aimed to evaluate the risk of carotid plaques according to the TyG index and thyroid function status in the general population.
Subjects and methods
Study population
This study retrospectively reviewed the data of 2,931 individuals who underwent carotid ultrasound as part of a comprehensive health examination at the Health Promotion Center of Soonchunhyang University Hospital between January 2016 and June 2018. Among these participants, 28 were excluded for abnormal free thyroxine (fT4) levels [fT4 <0.89 ng/dL (n = 9) and fT4 >1.78 ng/dL (n = 19)]. Finally, 2,903 subjects were eligible for analysis. All participants were categorized into six groups based on their TyG index and thyroid function status: LoTyG-SHyper (low TyG index with subclinical hyperthyroidism), LoTyG-Eu (low TyG index with euthyroidism), LoTyG-SHypo (low TyG index with subclinical hypothyroidism), HiTyG-SHyper (high TyG index with subclinical hyperthyroidism), HiTyG-Eu (high TyG index with euthyroidism) and HiTyG-SHypo (high TyG index with subclinical hypothyroidism).
The subjects’ anthropometric data, laboratory test results, and coded answers to self-reported questionnaires were stored in the electronic medical records. The requirement for informed consent for this study was waived by the institutional review board because we only accessed the database for analysis purposes and did not access personal identifying information. The study protocol was approved by the Institutional Review Board of Soonchunhyang University Hospital (approval number: 2022-09-006).
Clinical and laboratory measurements
Clinical variables for each individual were obtained from the medical records: sex, age, smoking, body mass index (BMI), systolic BP, diastolic BP, history of the medical disease (diabetes mellitus and hypertension) and use of medications (oral hypoglycemic agents, insulin and anti-hypertensive drugs).
Smoking status was evaluated using a questionnaire completed during an interview and participants were defined as current, former, or never smokers [27].
Height and weight were measured while the participants were wearing light clothing without shoes. BMI was calculated as the weight in kilograms divided by the square of height in meters (kg/m2). BP was measured using an automatic manometer with subjects in a sitting position All BP measurements were taken in triplicate, and the mean of the second and third measured values was used in the analyses.
After overnight fasting, blood samples were drawn from the antecubital vein into vacuum tubes and subsequently analyzed at a central, certified laboratory at Soonchunhyang University Hospital. Triglycerides, high-density lipoprotein (HDL) cholesterol and fasting glucose levels were measured using Cobas 8000 C702 (Roche Diagnostics System, Switzerland). Hemoglobin A1c (HbA1c) was measured using an immunoturbidimetric assay with a Cobas Integra 800 automatic analyzer (Roche Diagnostics) with a reference value range of 4.4–6.4%. HbA1c measurements were standardized to the reference method in the Diabetes Control and Complications Trial and according to the National Glycohemoglobin Standardization Program standards. Serum thyroid-stimulating hormone (TSH) levels were measured using an immunoradiometric assay with a TSH-CTK-3 kit (DiaSorin SpA, Saluggia, Italy) with a laboratory reference range of 0.3–4.0 mIU/L. Serum fT4 levels were assessed using a radioimmunoassay with an FT4 RIA kit (Immunotech, Prague, Czech Republic), with a laboratory reference range of 0.89–1.78 ng/dL.
Carotid ultrasound examination
A high-resolution B-mode ultrasound (EPIQ 5C or IE 33 USG systems; Philips, Andover, Massachusetts, USA) equipped with an 11 MHz linear array transducer was used to assess carotid artery plaques. The bilateral carotid arteries were scanned with the beam focused on the near and far walls of the distal 2 cm, or the common carotid artery proximal to its bifurcation. Both transverse and longitudinal images were obtained for extensively evaluated plaques. Carotid plaque presence was defined as focal abnormal wall thickness [intima-media thickness (IMT) >1.5 mm] or focal thickening of >50% of the surrounding IMT [28, 29]. To describe carotid plaque burden, the carotid plaque score was calculated as a total number of sites with plaques ranging from 0 to 6 (right- and left-sided common carotid artery, bifurcation and internal/external carotid artery) [30, 31]. All measurements were performed using the same device by the same experienced sonographer (SM Yoon, a registered diagnostic cardiac sonographer with 10 years of experience). The carotid ultrasound examination results were reviewed by two physicians (SS Kwon and DW Bang).
Definitions
The TyG index was calculated as ln[fasting triglycerides (mg/dL) × fasting blood glucose (mg/dL)/2] [7]. By dividing the 50th percentile according to the TyG index values, a TyG index value <8.625 was defined as a low TyG index group and a TyG index value ≥8.625 was defined as a high TyG index group.
Euthyroidism was defined as serum TSH and fT4 levels within the normal reference range. Subclinical hyperthyroidism was defined as TSH levels <0.3 mIU/L and normal fT4 levels, and subclinical hypothyroidism was defined as TSH levels >4.0 mIU/L and normal fT4 levels.
A significant carotid plaque was defined as a carotid plaque score ≥2.
Statistical analysis
Continuous variables are reported as medians with interquartile ranges, and categorical variables are presented as percentages (%). The demographic and biochemical characteristics of the study population with respect to the TyG index and thyroid function status were compared using the Mann-Whitney U-test or Kruskal-Wallis test for continuous variables and the χ2 test or Fisher’s exact test (for small cell values) for categorical variables.
Logistic regression analyses were used to estimate the odds ratios (ORs) with 95% confidence intervals (CIs) for the risk of carotid plaques by location and significant carotid plaques. All p values and 95% CI for OR were corrected using Bonferroni’s method due to multiple testing. Additional adjustments were made for confounding variables, such as sex, age (years), smoking (current smoker, ex-smoker or never smoker), obesity (BMI ≥25 kg/m2 or BMI <25 kg/m2), hypertension (BP ≥140/90 mmHg/antihypertensive medication or no) and diabetes mellitus (HbA1c ≥6.5%/antidiabetic medication or no).
All statistical analyses were performed using SPSS Statistics version 26.0 (IBM Corp., Chicago, IL, USA). Item analysis with a two-sided p value <0.05 was considered statistically significant.
Results
The baseline clinical and biochemical characteristics of the 2,903 participants are summarized in Table 1. Of these, 2,213 (76%) were male, with a median age of 52.0 (26.0–87.0) years. The median values of TSH and fT4 were 2.03 (0.0–25.23) mIU/L and 1.31 (0.89–1.78) ng/dL, respectively.
Subjects with a high TyG index were older, male, more likely to be current smokers, and tended to have a history of hypertension or diabetes mellitus than those with a low TyG index. They also had higher BMI, BP, HDL cholesterol, triglycerides, fasting glucose, HbA1c, TyG index, C-reactive protein, carotid IMT and carotid plaque scores than those with a low TyG index. There were no significant differences in TSH and fT4 levels between the low TyG index and high TyG index groups. There were also no significant differences in TSH and fT4 levels between the LoTyG-SHyper and HiTyG-SHyper groups, LoTyG-Eu and HiTyG-Eu groups, and LoTyG-SHypo and HiTyG-SHypo groups.
In the low TyG index group, there were statistically significant differences in terms of age, sex, and proportion of current smokers according to thyroid function status (Table 2A). In the high TyG index group, there were statistically significant differences in terms of sex, proportion of current smokers, and total cholesterol levels according to thyroid function status (Table 2B).
The proportion of participants with carotid plaques by location showed a significant difference among the six groups in the common carotid artery (p<0.001), bifurcation (p = 0.003), and internal carotid artery (p = 0.019) (Table 3). For the external carotid artery, there was no difference in the proportion of carotid plaques among the six groups.
In site-specific carotid plaque risk analysis, subjects in the LoTyG-SHypo, HiTyG-Eu and HiTyG-SHypo groups had a significantly higher risk of the common carotid artery and any site plaques than those in the LoTyG-Eu group. Subjects in the HiTyG-Eu and HiTyG-SHypo groups had a significantly higher risk of bifurcation plaques than those in the LoTyG-Eu group. Subjects in the HiTyG-Eu group had a higher risk of internal carotid artery plaques than those in the LoTyG-Eu group.
The proportion of subjects with significant carotid plaques was significantly different among the six groups and tended to increase significantly (Fig 1, p<0.001, p for trend<0.001).
We performed logistic regression analyses of the risk of significant carotid plaques among the subjects, using the LoTyG-Eu group as the reference category (Table 4).
Subjects with HiTyG-Eu (OR 1.453, 95% CI 1.240–1.702, p<0.001) and HiTyG-SHypo (OR 1.893, 95% CI 1.338–2.680, p<0.001) had a significantly greater risk of significant carotid plaques than those in the LoTyG-Eu group. Additional adjustment were made for confounding variables, such as sex, age, smoking, obesity, hypertension and diabetes mellitus. Only HiTyG-SHypo remained a significant risk factor for significant carotid plaques, even after such adjustments (OR 1.506, 95% CI 1.045–2.170, p = 0.028).
Discussion
In the present study, we found that the proportion of subjects with carotid plaques differed significantly according to insulin resistance and subclinical thyroid dysfunction. A high TyG index with subclinical hypothyroidism was associated with an increased probability of significant carotid plaques after adjusting for sex, age, smoking, obesity, hypertension and diabetes mellitus.
Recently, the TyG index has been considered an accessible and convenient measurement for estimating insulin resistance [32] and may be useful for predicting CVD events in clinical practice [33, 34]. The association between the TyG index and carotid plaques has been demonstrated in many studies [8–13]. The TyG index was positively associated with an elevated risk of carotid plaque prevalence [8, 9, 11, 13] and incidence [10, 12] in the general population. Consistent with previous studies, our results showed that a high TyG index was positively associated with carotid plaques and metabolic components such as obesity, high BP, low HDL cholesterol, high triglycerides and high glucose levels.
On the other hand, a recent study using a representative cohort of the Korean population reported that over hypothyroidism was correlated with an increased TyG index, and TSH was significantly correlated with the TyG index [26]. Another study using the same cohort found that the TyG index was associated with low-normal thyroid function in euthyroid Korean adults [25]. Therefore, we further investigated the risk of carotid plaques according to the TyG index, stratified by thyroid function status. The proportion of subjects with significant carotid plaques was significantly different according to insulin resistance and subclinical thyroid dysfunction. Subjects in the HiTyG-SHypo group had increased odds of the significant carotid plaques compared to those in the LoTyG-Eu group. This relationship remained statistically significant after adjusting for the major atherosclerotic risk factors.
Several studies have attempted to link subclinical thyroid dysfunction with carotid plaques [21–24]. A small case-control study in Macedonia reported that subclinical hypothyroidism was associated with carotid plaques, independent of the risk factors for atherosclerosis [24], which supports some of our data. A population-based study in Germany demonstrated that subjects with decreased serum TSH levels had increased odds for carotid plaques compared to those with normal serum TSH levels, but there was no associations between elevated serum TSH levels and carotid plaques [23]. Another population-based cross-sectional study in Italy found no correlation between subclinical thyroid dysfunction and carotid plaques [21]. Recently, Kim et al. examined the association between subclinical thyroid dysfunction and carotid plaques in a cross-sectional and longitudinal assessment of Korean healthy individuals [22]. At baseline, carotid plaques were more prevalent in the subclinical hypothyroidism group than in the euthyroidism group [22]. However, the effect of subclinical hypothyroidism on the cumulative incidence of new carotid plaques was not significantly different with follow-up time [22]. These inconsistent findings [21–24] are possibly due to regional differences in iodine intake, which may affect thyroid function, and differences in the study design and study population. In addition, since insulin resistance was not considered in previous studies [21–24], additional studies to validate our findings are needed to determine whether the risk of carotid plaques differs according to subclinical thyroid dysfunction.
The biological mechanisms that could link a high TyG index and subclinical hypothyroidism with carotid plaques within our study population remain to be elucidated. In terms of insulin resistance, high TyG index and subclinical hypothyroidism appear to be associated with carotid plaques. The TyG index is a reliable marker of insulin resistance [7], and subclinical hypothyroidism is known to exhibit insulin resistance similar to overt hypothyroidism [35]. Insulin resistance can play an important role in the development of atherosclerosis via several mechanisms, including endothelial cell dysfunction [36, 37], proliferation and migration of vascular smooth muscle cells [38], modification of the synthesis and release of lipoproteins, inflammation, and reactive oxygen species formation [39, 40]. Regarding thyroid hormones themselves, subclinical hypothyroidism may be associated with atherosclerosis, as TSH directly stimulates hepatic gluconeogenesis [41] and cholesterol synthesis [42, 43], and leptin secretion in adipocytes [44]. In addition, thyroid hormone therapy has been shown to be effective in preventing the progression of atherosclerosis [45, 46] and contributing to endothelial-dependent vasodilation [47].
Despite the strength of large samples and control of extensive data on insulin resistance and several potential confounding factors, this study has some limitations. Due to its cross-sectional and retrospective nature, causal inferences could not be drawn. This study also lacked information on other exposures, including alcohol intake, physical activity, and medication with anti-thyroid drugs, thyroid hormones, or statins. Therefore, we cannot rule out the possibility of residual confounding variables for some measured and unmeasured factors. As subclinical thyroid dysfunction may be temporary, repeated measurement of thyroid function could provide a reliable result. A single measurement of thyroid function may have resulted in the inclusion of transient subclinical thyroid dysfunction. Therefore, additional prospective longitudinal studies are required.
In conclusion, our finding revealed a high TyG index with subclinical hypothyroidism is associated with an increased risk of carotid plaques in the general population. Early recognition of clinically useful biomarkers for carotid plaques could help identify subjects at high risk of CVD who may benefit from earlier medical treatment and lifestyle modifications.
References
- 1. Nambi V, Brunner G, Ballantyne CM. Ultrasound in cardiovascular risk prediction: don’t forget the plaque! J Am Heart Assoc. 2013; 2(2):e000180. pmid:23598274.
- 2. Yeboah J, McClelland RL, Polonsky TS, Burke GL, Sibley CT, O’Leary D, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. Jama. 2012; 308(8):788–795. pmid:22910756.
- 3. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019; 140(11):e563–e595. pmid:30879339.
- 4. Inaba Y, Chen JA, Bergmann SR. Carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: a meta-analysis. Atherosclerosis. 2012; 220(1):128–133. pmid:21764060.
- 5. Tada H, Nakagawa T, Okada H, Nakahashi T, Mori M, Sakata K, et al. Clinical Impact of Carotid Plaque Score rather than Carotid Intima-Media Thickness on Recurrence of Atherosclerotic Cardiovascular Disease Events. J Atheroscler Thromb. 2020; 27(1):38–46. pmid:31105127.
- 6. Hanley AJ, Williams K, Stern MP, Haffner SM. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care. 2002; 25(7):1177–1184. pmid:12087016.
- 7. Guerrero-Romero F, Simental-Mendía LE, González-Ortiz M, Martínez-Abundis E, Ramos-Zavala MG, Hernández-González SO, et al. The product of triglycerides and glucose, a simple measure of insulin sensitivity. Comparison with the euglycemic-hyperinsulinemic clamp. J Clin Endocrinol Metab. 2010; 95(7):3347–3351. pmid:20484475.
- 8. Irace C, Carallo C, Scavelli FB, De Franceschi MS, Esposito T, Tripolino C, et al. Markers of insulin resistance and carotid atherosclerosis. A comparison of the homeostasis model assessment and triglyceride glucose index. Int J Clin Pract. 2013; 67(7):665–672. pmid:23758445.
- 9. Wang A, Tian X, Zuo Y, Zhang X, Wu S, Zhao X. Association between the triglyceride-glucose index and carotid plaque stability in nondiabetic adults. Nutr Metab Cardiovasc Dis. 2021; 31(10):2921–2928. pmid:34353702.
- 10. Wu Z, Wang J, Li Z, Han Z, Miao X, Liu X, et al. Triglyceride glucose index and carotid atherosclerosis incidence in the Chinese population: A prospective cohort study. Nutr Metab Cardiovasc Dis. 2021; 31(7):2042–2050. pmid:34045133.
- 11. Li W, Chen D, Tao Y, Lu Z, Wang D. Association between triglyceride-glucose index and carotid atherosclerosis detected by ultrasonography. Cardiovasc Diabetol. 2022; 21(1):137. pmid:35864527.
- 12. Lu YK, Dong J, Li YL, Liu YH, Hu LK, Chu X, et al. Association between insulin resistance and incidence of carotid atherosclerotic plaque: A cohort study. Nutr Metab Cardiovasc Dis. 2022; 32(4):981–993. pmid:35168827.
- 13. Wang A, Li Y, Zhou L, Liu K, Li S, Song B, et al. Triglyceride-Glucose Index Is Related to Carotid Plaque and Its Stability in Nondiabetic Adults: A Cross-Sectional Study. Front Neurol. 2022; 13:823611. pmid:35401402.
- 14. Krotkiewski M. Thyroid hormones in the pathogenesis and treatment of obesity. Eur J Pharmacol. 2002; 440(2–3):85–98. pmid:12007527.
- 15. Kutty KM, Bryant DG, Farid NR. Serum lipids in hypothyroidism—a re-evaluation. J Clin Endocrinol Metab. 1978; 46(1):55–56. pmid:109455.
- 16. Chait A, Bierman EL, Albers JJ. Regulatory role of triiodothyronine in the degradation of low density lipoprotein by cultured human skin fibroblasts. J Clin Endocrinol Metab. 1979; 48(5):887–889. pmid:219014.
- 17. Torrance CJ, Devente JE, Jones JP, Dohm GL. Effects of thyroid hormone on GLUT4 glucose transporter gene expression and NIDDM in rats. Endocrinology. 1997; 138(3):1204–1214. pmid:9048628.
- 18. Fommei E, Iervasi G. The role of thyroid hormone in blood pressure homeostasis: evidence from short-term hypothyroidism in humans. J Clin Endocrinol Metab. 2002; 87(5):1996–2000. pmid:11994331.
- 19. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med. 2001; 344(7):501–509. pmid:11172193.
- 20. Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis. J Clin Endocrinol Metab. 2003; 88(6):2438–2444. pmid:12788839.
- 21. Delitala AP, Filigheddu F, Orrù M, AlGhatrif M, Steri M, Pilia MG, et al. No evidence of association between subclinical thyroid disorders and common carotid intima medial thickness or atherosclerotic plaque. Nutr Metab Cardiovasc Dis. 2015; 25(12):1104–1110. pmid:26615224.
- 22. Kim H, Kim TH, Kim HI, Park SY, Kim YN, Kim S, et al. Subclinical thyroid dysfunction and risk of carotid atherosclerosis. PLoS One. 2017; 12(7):e0182090. pmid:28750042.
- 23. Dörr M, Empen K, Robinson DM, Wallaschofski H, Felix SB, Völzke H. The association of thyroid function with carotid artery plaque burden and strokes in a population-based sample from a previously iodine-deficient area. Eur J Endocrinol. 2008; 159(2):145–152. pmid:18495692.
- 24. Valentina VN, Marijan B, Chedo D, Branka K. Subclinical hypothyroidism and risk to carotid atherosclerosis. Arq Bras Endocrinol Metabol. 2011; 55(7):475–480. pmid:22147096.
- 25. Choi W, Park JY, Hong AR, Yoon JH, Kim HK, Kang HC. Association between triglyceride-glucose index and thyroid function in euthyroid adults: The Korea National Health and Nutritional Examination Survey 2015. PLoS One. 2021; 16(7):e0254630. pmid:34264998.
- 26. Choi YM, Kim MK, Kwak MK, Kim D, Hong EG. Association between thyroid hormones and insulin resistance indices based on the Korean National Health and Nutrition Examination Survey. Sci Rep. 2021; 11(1):21738. pmid:34741077.
- 27. Park S, Kim WG, Jeon MJ, Kim M, Oh HS, Han M, et al. Serum thyroid-stimulating hormone levels and smoking status: Data from the Korean National Health and Nutrition Examination Survey VI. Clin Endocrinol (Oxf). 2018; 88(6):969–976. pmid:29604104.
- 28. Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr. 2008; 21(2):93–111; quiz 189–190. pmid:18261694.
- 29. Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N, et al. Mannheim carotid intima-media thickness consensus (2004–2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006. Cerebrovasc Dis. 2007; 23(1):75–80. pmid:17108679.
- 30. Hollander M, Bots ML, Del Sol AI, Koudstaal PJ, Witteman JC, Grobbee DE, et al. Carotid plaques increase the risk of stroke and subtypes of cerebral infarction in asymptomatic elderly: the Rotterdam study. Circulation. 2002; 105(24):2872–2877. pmid:12070116.
- 31. Kwon SS, Yoon SY, Jeong SY, Lee MY, Kim KH, Lee N, et al. Neutrophil-lymphocyte ratio and carotid plaque burden in patients with essential thrombocythemia and polycythemia vera. Nutr Metab Cardiovasc Dis. 2022; 32(8):1913–1916. pmid:35606226.
- 32. Sánchez-García A, Rodríguez-Gutiérrez R, Mancillas-Adame L, González-Nava V, Díaz González-Colmenero A, Solis RC, et al. Diagnostic Accuracy of the Triglyceride and Glucose Index for Insulin Resistance: A Systematic Review. Int J Endocrinol. 2020; 2020:4678526. pmid:32256572.
- 33. Li S, Guo B, Chen H, Shi Z, Li Y, Tian Q, et al. The role of the triglyceride (triacylglycerol) glucose index in the development of cardiovascular events: a retrospective cohort analysis. Sci Rep. 2019; 9(1):7320. pmid:31086234.
- 34. Jin JL, Cao YX, Wu LG, You XD, Guo YL, Wu NQ, et al. Triglyceride glucose index for predicting cardiovascular outcomes in patients with coronary artery disease. J Thorac Dis. 2018; 10(11):6137–6146. pmid:30622785.
- 35. Maratou E, Hadjidakis DJ, Kollias A, Tsegka K, Peppa M, Alevizaki M, et al. Studies of insulin resistance in patients with clinical and subclinical hypothyroidism. Eur J Endocrinol. 2009; 160(5):785–790. pmid:19141606.
- 36. Vicent D, Ilany J, Kondo T, Naruse K, Fisher SJ, Kisanuki YY, et al. The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance. J Clin Invest. 2003; 111(9):1373–1380. pmid:12727929.
- 37. Rask-Madsen C, Li Q, Freund B, Feather D, Abramov R, Wu IH, et al. Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice. Cell Metab. 2010; 11(5):379–389. pmid:20444418.
- 38. Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 2011; 14(5):575–585. pmid:22055501.
- 39. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006; 116(7):1793–1801. pmid:16823477.
- 40. Razani B, Chakravarthy MV, Semenkovich CF. Insulin resistance and atherosclerosis. Endocrinol Metab Clin North Am. 2008; 37(3):603–621, viii. pmid:18775354.
- 41. Wang T, Xu J, Bo T, Zhou X, Jiang X, Gao L, et al. Decreased fasting blood glucose is associated with impaired hepatic glucose production in thyroid-stimulating hormone receptor knockout mice. Endocr J. 2013; 60(8):941–950. pmid:23665701.
- 42. Tian L, Song Y, Xing M, Zhang W, Ning G, Li X, et al. A novel role for thyroid-stimulating hormone: up-regulation of hepatic 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase expression through the cyclic adenosine monophosphate/protein kinase A/cyclic adenosine monophosphate-responsive element binding protein pathway. Hepatology. 2010; 52(4):1401–1409. pmid:20648556.
- 43. Zhang X, Song Y, Feng M, Zhou X, Lu Y, Gao L, et al. Thyroid-stimulating hormone decreases HMG-CoA reductase phosphorylation via AMP-activated protein kinase in the liver. J Lipid Res. 2015; 56(5):963–971. pmid:25713102.
- 44. Menendez C, Baldelli R, Camiña JP, Escudero B, Peino R, Dieguez C, et al. TSH stimulates leptin secretion by a direct effect on adipocytes. J Endocrinol. 2003; 176(1):7–12. pmid:12525244.
- 45. Perk M, O’Neill BJ. The effect of thyroid hormone therapy on angiographic coronary artery disease progression. Can J Cardiol. 1997; 13(3):273–276. pmid:9117915.
- 46. Monzani F, Caraccio N, Kozàkowà M, Dardano A, Vittone F, Virdis A, et al. Effect of levothyroxine replacement on lipid profile and intima-media thickness in subclinical hypothyroidism: a double-blind, placebo- controlled study. J Clin Endocrinol Metab. 2004; 89(5):2099–2106. pmid:15126526.
- 47. Napoli R, Guardasole V, Angelini V, Zarra E, Terracciano D, D’Anna C, et al. Acute effects of triiodothyronine on endothelial function in human subjects. J Clin Endocrinol Metab. 2007; 92(1):250–254. pmid:17047021.