Front. Cardiovasc. Med. Frontiers in Cardiovascular Medicine Front. Cardiovasc. Med. 2297-055X Frontiers Media S.A. 10.3389/fcvm.2023.1075844 Cardiovascular Medicine Original Research Association between thyroid cancer and cardiovascular disease: A meta-analysis TsaiWen-Hsuan 1 ZengYi-Hong 1 2 LeeChun-Chuan 1 2 ChienMing-Nan 1 2 LiuSung-Chen 1 2 ChienKuo-Liong 3 ChengShih-Ping 4 TsengPo-Jung 5 TsaiMing-Chieh 1 2 3 * Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan Department of Medicine, MacKay Medical College, New Taipei City, Taiwan Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan Department of General Surgery, Mackay Memorial Hospital, Taipei, Taiwan Division of Cardiovascular Surgery, Department of Surgery, Hsin Chu Armed Force Hospital, Hsinchu, Taiwan

Edited by: Bernadette Biondi, University of Naples Federico II, Italy

Reviewed by: Yen-Wen Wu, Far Eastern Memorial Hospital, Taiwan Serena Ippolito, Ospedale del Mare, Italy Andres Daniele, Instituto de Oncología Ángel H. Roffo, Argentina

 Correspondence: Ming-Chieh Tsai r07849036@ntu.edu.tw

Specialty Section: This article was submitted to Cardio-Oncology, a section of the journal Frontiers in Cardiovascular Medicine

Abbreviations TC, thyroid cancer; RAI, Radioactive iodine; TSH, thyroid-stimulating hormone; CAD, coronary artery disease; CVD, cardiovascular disease; Af, atrial fibrillation; TKI, tyrosine kinase inhibitor; RCT, randomized controlled trial.

 03032023 2023 101075844 21102022 16022023 © 2023 Tsai, Zeng, Lee, Chien, Liu, Chien, Cheng, Tseng and Tsai. 2023Tsai, Zeng, Lee, Chien, Liu, Chien, Cheng, Tseng and Tsai

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 Objective

To determine the association between thyroid cancer and coronary artery disease, atrial fibrillation, cerebrovascular disease, and cardiovascular disease mortality.

Methods

The PubMed, Embase, and Cochrane Library databases were searched for eligible studies from inception to September 22, 2022. Keywords included “thyroid cancer”, “atrial fibrillation”, “coronary artery disease”, “cerebrovascular disease”, and “mortality”. Primary outcomes included the incidence of coronary artery disease, cerebrovascular disease, atrial fibrillation, and cardiovascular disease mortality among patients with thyroid cancer. Secondary outcomes included cardiovascular disease events among those with thyroid cancer that received or did not receive radioactive iodine or lenvatinib. Estimates were pooled using fixed- and random-effects meta-analysis.

Results

A total of 771,220 patients who underwent thyroidectomy in 15 studies were included. Risk for cerebrovascular disease (risk ratio [RR] 1.15 [95% confidence interval (CI) 1.10–1.21]) and atrial fibrillation [RR 1.59 (95% CI: 1.45–1.73)] were significantly increased. Risk for coronary artery disease was significantly increased [RR 1.12 (95% CI: 1.08–1.17)] in the common effect model. Cardiovascular disease mortality associated with thyroid cancer was not significant [RR 0.93 (95% CI: 0.59–1.45)]. Radioactive iodine had a neutral effect on cardiovascular disease [RR 1.00 (95% CI: 0.87–1.16)], and there was no beneficial nor harmful effect among different RAI doses.

Conclusions

Thyroid cancer was significantly associated with a higher risk for cerebrovascular disease and atrial fibrillation; however, the hazard risk was not different between patients with and without radioactive iodine treatment. Thyroid cancer treatment should be individualized considering the potential harms and benefits to cardiovascular health.

 thyroid cancer cardiovascular disease thyroxine radioactive iodine tyrosine kinase inhibitors 110-2314-B-195-004Ministry of Science and TechnologyMOST Introduction

The incidence of thyroid cancer (TC) is ranked 11th according to the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer (1). The incidence of TC has been increasing over the past few decades (2) and, if recent trends persist, TC may become the fourth most common cancer by 2030 in the United States (3). Such an increase is likely due to improved detection and diagnosis, which largely or totally reflects the over-diagnosis of indolent disease (2). The survival rate, particularly for papillary carcinoma, is extremely high (>98% five-year survival rate in Europe or North America), resulting in comparatively low mortality rates (2). The 10-year relative survival rates for patients with papillary, follicular, and Hurthle cell carcinomas were 93%, 85%, and 76%, respectively (4). Primary management of TC includes surgery, radioactive iodine (RAI), and thyroid-stimulating hormone (TSH) suppression therapy, according to American Thyroid Association (ATA) risk stratification system (5). In 2022, a randomized controlled trial of 776 patients with low-risk TC demonstrated that after thyroidectomy, active surveillance without RAI was non-inferior to RAI regarding the occurrence of functional, structural, and biologic events at third year (6). Active surveillance has been advocated as an alternative to active management for low-risk papillary thyroid micro-carcinoma (PTMC) (7). Despite good prognosis, 4%–16% of patients with PTMC develop recurrent disease, with many of which developing distant metastasis (8–10). A cohort of 407 patients with PTMC revealed that patients with lymph node metastasis who did not receive I-131 had a 5-year recurrence-free survival of 42.9% vs. 93.2% (P < 0.0001) for patients who received I-131 (11). On the other hand, patients with radioiodine refractory (RR)-DTC have a 5-year survival rate of as low as 10% (12). Tyrosine kinase inhibitors, such as sorafenib and lenvatinib, were approved for the treatment of patients with RR-DTC (13, 14). To sum up, the treatment strategy for TC should be individualized.

173,710 patients with TC from the Surveillance, Epidemiology, and End Results (SEER) database showed that 29.1% and 21.7% of death were attributable to TC and cardiovascular disease (CVD) (15). Older age, male sex, non-white race, unmarried status, and advanced stage were independent predictors of CVD mortality, while receiving surgery and radiotherapy were protective against CVD mortality (15). On the other hand, 30,778 patients with TC from Taiwan's National Health Insurance Research Database revealed that the primary cause of death was TC mortality (31.2%), followed by other malignancy-related mortality (29.9%) and CVD mortality (12.3%) (16). Some research has suggested that the management of TC could lead to long-term cardiovascular risks. For example, studies have demonstrated that patients with TC had higher odds (hazard ratio [HR] 1.16 [95% confidence interval (CI) 1.05–1.28]) for CVD (17) and higher odds [HR 1.29 (CI: 1.06–1.57)] for atrial fibrillation (Af) (18) compared with the general healthy population. In contrast, however, another study failed to find an association between a high risk for CVD or Af and patients with TC (19). The association between tyrosine kinase inhibitors (TKIs) and CVD in patients with TC is still lacking.

Owing to the increasing incidence and relatively good prognosis of TC, an updated and comprehensive quantitative review is needed to assess the long-term effects on the cardiovascular system among patients with TC after thyroidectomy, RAI and TKIs. We aimed to examine the incidence of coronary artery disease (CAD), Af, cerebrovascular disease and CVD mortality in patients with TC; and the risk for CVD among patients who underwent RAI or lenvatinib (TKI).

 Methods Information sources and search strategy

Two authors (W.H.T and M.C.T) independently identified articles published before September 22nd, 2022, that investigated and reported on “thyroid cancer”, “atrial fibrillation”, “coronary artery disease”, “cerebrovascular disease”, and “mortality”. (Supplementary Table S1) by systematically searching the PubMed (Medline), Embase, and Cochrane Library databases. The authors screened the titles and abstracts of studies and identified those for inclusion eligibility using approaches prescribed by the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology reporting guidelines (20).

 Eligibility criteria

Two reviewers initially screened the titles and abstracts of all retrieved articles for eligibility. Studies with the following characteristics were excluded: target population(s) not related to TC; data that did not address the outcome of interest; reviews, meta-analyses, or commentaries. The inclusion criteria included all patients with TC that received either thyroidectomy, thyroxine, RAI or TKIs. After initially screening articles for inclusion based on title and abstract, the full text of each was reviewed. Disagreements were resolved by the third author. The PECOS framework was demonstrated in Supplementary Table S2 (21).

 Data extraction and quality assessment

The following information was extracted from each study: year of publication; author(s); country; number of participants (TC/control); proportion of women; age at diagnosis; mean years' follow-up; statistical analysis; and adjusted variable and outcomes with hazard ratio (HR). The Risk of Bias in Non-randomized Studies‒Exposure (ROBINS-E) was used to assess the risk of bias (22).

 Data synthesis and statistical analysis

Outcome ascertainment was variably defined as CAD, cerebrovascular disease, Af, and CVD mortality. In the first analysis, pooled risk estimates of CAD, cerebrovascular disease, Af and CVD mortality between patients with TC and the general healthy population were calculated. The risk for CVD between TC patients with and without RAI or lenvatinib was also examined. We extracted the number of CVD adverse events among the clinical trials and calculated the difference in the observed percentages of patients. We used logistic regression to perform the odds ratio with 95% confidence interval (CIs) of the CVD adverse events among clinical trials. When ≥ 2 studies assessed the same outcome, results were pooled using both fixed- and random-effect meta-analysis, which specifically accounted for heterogeneity among studies. Extracted pooled HRs for individual outcomes were combined to construct summary pooled HRs. Heterogeneity was assessed using standard chi-squared tests and the I2 statistic, for which I2 > 75% indicated substantial heterogeneity. Random-effect meta-regression was performed to investigate sources of heterogeneity (mean age, women proportion, follow up years).

Linear dose responses were modeled using the method by Greenland and Longnecker with RRs (95% CIs) from RAI dose categories to determine the association with the risk of CVD (23). Two studies (24, 25) were included for information regarding the association. Doses were defined as the mean exposure in each reported category. The width of the adjacent interval was used as an upper or lower cut-off value with open-ended extreme categories. The Wald test for departure from linearity association was conducted and significance was defined at P < 0.10 (2-sided) (26) which leads to further non-linear analysis. The pairwise analyses were significant based on P < 0.05. Non-linear dose-response relationship was assessed using restricted cubic splines with three knots at 10%, 50%, and 90% percentiles of the distribution.

Bias secondary to small study effects was assessed using visual inspection of funnel plots but could not be examined by Egger test plots because there was fewer than 10 studies. Statistical significance was defined as two-sided P < 0.05. All analyses were performed using R version 3.5.1 (R Project for Statistical Computing).

 Results Study identification and selection

As shown in Figure 1, 16,001 studies were retrieved in the literature search, of which 300 articles were duplicates, leaving 15,701 articles to assess for inclusion. An additional 14,000 studies were excluded based on title and/or abstract, and another 1,686 articles excluded based on full-text review, which resulted in 15 studies for quantitative analysis. Among these 15 studies, 3 of the articles included patients without thyroidectomy (17, 24, 27), with the percentage of 22%, 35.5%, and 2.2%, respectively. There were five studies (17, 19, 28–30) including 420,175 patients for evaluation of CAD; six studies (17, 19, 27–30) including 439,468 patients for evaluation of cerebrovascular disease; six studies (17, 19, 27–29, 31) including 385,150 patients for evaluation of Af; five studies (15–18, 25) including 310,475 patients for evaluation of CVD mortality; five studies (6, 24, 25, 27, 32) including 48,328 patients to examine the risk for CVD between patients with TC who did and did not undergo RAI therapy. One randomized clinical trial with 392 patients was included to examine the risk for CVD between patients with TC who did and did not receive lenvatinib (13). Five studies (17, 18, 28, 31, 33) were included to assess the association between levothyroxine dose or TSH level and CVD, Af and CVD mortality. The country, participant number, women proportion, mean age, follow-up years, adjusted variables, and outcome ascertainment for the included studies are summarized in Table 1. Risk of bias for all 15 individual studies are listed in Supplementary Table S3.

The process of literature search based on the PRISMA statement.

Characteristics of studies included in meta-analysis stratified by the risk of CAD, cerebrovascular disease, Af, CVD mortality, different TSH level (mU/liter) control, levothyroxine dose (μg/day) response, RAI (with or without) and cumulative RAI dose, lenvatinib (with or without).

Study Country Number (DTC/Control) Women%, Age (SD), Follow up (yrs) Preexisting CVD Adjusted variable Outcome HR
The risk of CAD among patients with DTC compared with healthy control
Pajamäki, 2018 Finland 901/4,485 81, 48 (16), 18.8 The results did not change when the subjects with a prevalent CVD were excluded Prevalent CVD 0.94 (0.78–1.12)
Suh, 2019 Korea 182,419/182,419 84.2, 47 (11.3), 4.3 Excluded Age, sex, income, monthly insurance, residence, disability 1.15 (1.1–1.22)
Toulis, 2019 UK 3,009/11,303 75.8, 50.7 (16.1), 4.8 Excluded Age, BMI, sex, smoking status, Townsend deprivation index, hypertension, diabetes and lipid-lowering medication 1.04 (0.8–1.36)
Zoltek, 2020 Sweden 6,000/ 73.7, 54 NA NA SIR*: 0.97 (0.84–1.11)
Izkhakov, 2019 Israel 5,677/23,962 78.6, 50 (16), 7.6 3%/8.2% Age, sex, hypertension, diabetes mellitus, current smoking, dyslipidemia and previous cardiovascular disease 1.2 (1.08–1.34)
The risk of cerebrovascular disease among patients with DTC compared with healthy control
Pajamäki, 2018 Finland 901/4,485 81, 48 (16), 18.8 The results did not change when the subjects with a prevalent CVD were excluded Prevalent CVD 0.98 (0.78–1.24)
Blackburn, 2017 USA 3,706/15,587 77.9, 46 Excluded Age, sex, birth state, BMI, race, CCI <40 y/o: 2.26 (0.75–6.78)>40 y/o: 1.20 (0.88–1.64)
Suh, 2019 Korea 182,419/182,419 84.2, 47 (11.3), 4.3 Excluded Age, sex, income, monthly insurance, residence, disability 1.15 (1.09–1.22)
Toulis, 2019 UK 3,009/11,303 75.8, 50.7 (16.1), 4.8 Excluded Age, BMI, sex, smoking status, Townsend deprivation index, hypertension, diabetes and lipid-lowering medication 1.34 (1.05-1.72)
Izkhakov1, 2019 Israel 5,677/23,962 78.6, 50 (16), 7.6 3%/8.2% Age, sex, hypertension, diabetes mellitus, current smoking, dyslipidemia and previous cardiovascular disease 1.19 (1.04–1.37)
Zoltek, 2020 Sweden 6,000/ 73.7, 54 NA NA SIR*: 1.14 (1.01–1.29)
The risk of atrial fibrillation among patients with DTC compared with healthy control
Hesselink, 2015 Netherlands 518/1,563 74.4, 48.6 (14), 10.5 1.2%/1.6% Age, sex, HTN, BMI, Hx of CAD and HF 2.47 (1.55–3.95)
Blackburn, 2017 USA 3,706/15,587 77.9, 46 Excluded Age, sex, birth state, BMI, race, CCI 1.05 (0.66–1.66)
Pajamäki, 2018 Finland 901/4,485 81, 48 (16), 18.8 The results did not change when the subjects with a prevalent CVD were excluded Prevalent CVD 1.29 (1.06–1.57)
Suh, 2019 Korea 182,419/182,419 84.2, 47 (11.3), 4.3 Excluded Age, sex, income, monthly insurance, residence, disability Levothyroxine <115 μg/day, HR: 1.43 (1.27–1.62); Levothyroxine 115–144 μg/day, HR: 1.41 (1.26–1.58); Levothyroxine 145–169 μg/day, HR: 1.66 (1.49–1.85); Levothyroxine ≥170 μg/day, HR: 1.78 (1.60–1.98)
Toulis, 2019 UK 3,009/11,303 75.8, 50.7 (16.1), 4.8 Excluded Age, BMI, sex, smoking status, Townsend deprivation index, hypertension, diabetes and lipid-lowering medication 1.71 (1.36-2.15)
Zoltek, 2020 Sweden 6,000/ 73.7, 54 NA NA SIR*: 1.66 (1.41–1.94)
The risk of CVD mortality among patients with DTC compared with healthy control
Hesselink, 2013 Netherlands 524/1,572 74.4, 48.6 (14), 10.5 2.5%/2.9% Age, sex, HTN, BMI, Hx of CAD and HF 3.35 (1.66–6.74)
Pajamäki, 2018 Finland 901/4,485 81, 48 (16), 18.8 The results did not change when the subjects with a prevalent CVD were excluded Prevalent CVD 0.73 (0.58–0.92)
Kim, 2020 Korea 4,082/12,246 78.6, 46, 3 3.2%/3.2% BMI, socioeconomical, smoking, alcohol, HTN, DM and dyslipidemia 0.5 (0.22–1.16)
Lu, 2021 Taiwan 30,778 /92,334 75.8, 50.7 (16.1), 5.67 2.2%/4.5% Age, sex, ischemic heart disease, ischemic stroke, hemorrhagic stroke, hyperlipidemia, DM, HTN, and occupation 0.56 (0.42–0.76)
Du, 2021 USA 163,553/ 76.7, 48, 8.5 NA NA PTC: 0.57 (0.55–0.59)FTC: 1.14 (1.06–1.23)Hürthle cell TC: 1.47 (1.30–1.67)
Adjusted HRs for CVD by with or without RAI
Pajamäki, 2018 Finland 901/4,485 81, 48 (16), 18.8 The results did not change when the subjects with a prevalent CVD were excluded Prevalent CVD CVD: TC with I131 vs. control: HR 1.18 (1.05–1.31); TC without I131 vs. control: HR 1.07 (0.85–1.34)
Blackburn, 2017 USA 3,706/15,587 77.9, 46 Excluded Age, sex, birth state, BMI, race, CCI 1.13 (0.99–1.29)
Lin, 2017 Taiwan 5,052/5,052 (with/without RAI) 84.6, 49.4 (13.8) 11.7%/11.8% Age, sex, hypertension, hyperlipidemia, diabetes, COPD, CAD, alcohol-related illness, asthma 0.97 (0.73–73.30)
Suh, 2019 Korea 182,419/182,419 84.2, 47 (11.3), 4.3 Excluded Age, sex, income, monthly insurance premiu, residence, disability CVD: TC with I131 vs. control: HR 1.18 (1.11–1.26); TC without I131 vs. control: HR 1.15 (1.06–1.25)
Suh, 2019 Korea 182,419/182,419 84.2, 47 (11.3), 4.3 Excluded Age, sex, income, monthly insurance premiu, residence, disability Ischemic stroke: TC with I131 vs. control: HR 1.13 (1.06–1.21); TC without I131 vs. control: HR 1.18 (1.09–1.28)
Kim, 2020 Korea 2,533/2,312 (with/without RAI) 78.6, 46, 3 7.1%/7.6% Age, sex, body mass index, socioeconomical, smoking, alcohol, levothyroxine, and history of HTN, DM, dyslipidemia, CVD CVD: HR 0.87 (0.71–1.07); ischemic stroke: HR 0.83 (0.51–1.34); ischemic heart disease: HR 0.90 (0.71–1.13)
Leboulleux, 2022 France 389/387 (with/without RAI) 82.8, 52.4, 3 NA Randomized controlled trial OR: 0.52 (0.05–5.61) with RAI: 1 heart attack, without RAI: 1 transient ischemic stroke, 1 stroke
Kao, 2021 Taiwan 11,889/1,421 80, 47.3, 5.16 Excluded Age, sex, DM, CKD, hyperlipidemia, and modified Charlson comorbidity index score 0.99 (0.84–1.16)
Adjusted HRs for CVD by with or without tyrosine kinase inhibitors
Schlumberger, 2015 (SELECT): Lenvatinib USA, Europe, Asia, and Australia 261/131 49, 63, 1.5 NA Randomized controlled trial 3.54 (1.03–12.13)
Brose, 2014 (DECISION): Sorafenib 18 countries 207/210 52.3, 63, 0.9 NA Randomized controlled trial Sorafenib: 2 CAD, 0 AfPlacebo: 0 CAD, 2 Af
Adjusted HRs for CVD by TSH (mU/liter) compared with healthy control
Pajamäki, 2018 Finland 901/4,485 81, 48 (16), 18.8 The results did not change when the subjects with a prevalent CVD were excluded Prevalent CVD TSH < 0.1, HR: 1.27 (1.03–1.58); TSH: 0.1–0.5, HR: 1.04 (CI 0.83–1.31); TSH > 0.5, HR: 1.31, (0.98–1.77)
Adjusted HRs for CVD by Levothyroxine dose (μg/day)
Suh, 2019 Korea 182,419/182,419 84.2, 47 (11.3), 4.3 Excluded age, sex, income, monthly insurance premiu, residence, disability CAD: Levothyroxine <115 μg/day, HR: 1.41 (1.26–1.58); Levothyroxine 115–144 μg/day, HR: 1; Levothyroxine 145–169 μg/day, HR: 1.61 (1.45–1.8); Levothyroxine ≥170 μg/day, HR: 2.15 (1.94–2.39)
Suh, 2019 Korea 182,419/182,419 84.2, 47 (11.3), 4.3 Excluded age, sex, income, monthly insurance premium, residence, disability Ischemic stroke: Levothyroxine <115 μg/day, HR: 1.31 (1.16–1.47); Levothyroxine 115–144 μg/day, HR: 1; Levothyroxine 145–169 μg/day, HR: 1.63 (1.46–1.82); Levothyroxine ≥170 μg/day, HR: 2.15 (1.94–2.39)
Adjusted HRs for atrial fibrillation by TSH (mU/liter)
Wang, 2015 USA 465/306 (TSH ≤ 0.4/TSH > 0.4) 73.8, 48 (14), 6.5 Af excluded age, sex, RAI, and ATA risk category TSH ≤ 0.4 v.s. TSH > 0.4, HR 1.02 (0.54–1.91)
Adjusted HRs for atrial fibrillation by each 10-fold decrease in TSH level
Hesselink, 2015 Netherlands 518/1,563 74.4, 48.6 (14), 10.5 1.2%/1.6% age, sex, HTN, BMI, Hx of CAD and HF 1.01 (0.71–1.44)
Adjusted HRs for CVD mortality and total mortality by each 10-fold decrease in TSH level
Hesselink, 2013 Netherlands 524/1,572 74.4, 48.6 (14), 10.5 2.5%/2.9% age, sex, HTN, BMI, Hx of CAD and HF CVD mortality: HR 3.08 (1.32–7.21); Total mortality: 1.43 (0.97–2.12)

SIR: standardized incidence ratio.

 Risk for CAD, cerebrovascular disease, AF, and CVD mortality compared between patients with TC and healthy controls in the general population

Meta-analytic pooling of hazard estimates of CAD between patients with TC and the general healthy population in 5 studies (Figure 2) revealed a non-significantly increased risk [RR 1.08 (95% CI 0.98‒1.19)] in the random effect model. However, a significantly increased risk [RR 1.12 (95% CI: 1.08‒1.17)] was noted in the common effect model. Patients with TC had significantly higher risk of cerebrovascular disease [RR 1.15 (95% CI: 1.10‒1.21)] and Af [RR 1.59 (95% CI: 1.45‒1.73)] (Figure 2). Of the 5 studies (Figure 2) that investigated CVD mortality associated with TC, there was no significantly decreased risk [RR 0.93 (95% CI: 0.59‒1.45)].

Forest plots for meta-analysis of the association between thyroid cancer and CAD; cerebrovascular disease; Af; CVD mortality; and the risk of CVD among patients with TC with and without RAI or lenvatinib.

 Risk for CVD among DTC patients who did and did not undergo RAI or lenvatinib

The pooled risk for CVD between patients with TC that received or did not receive RAI in 5 studies (Figure 2) demonstrated no significantly increased risk [RR 1.00 (95% CI: 0.87‒1.16)]. A randomized controlled trial (RCT) (Figure 2) suggested a significantly increased risk of lenvatinib for CVD [RR 3.54 (95% CI: 1.03‒12.13)]. Figure 3A showed the dose-response association of RAI cumulative dose and the incidence of CVD. The linear model was demonstrated by the solid line and 95% CI was represented by the dotted lines. Data from 2 cohorts (24, 25) with a dose range of 0 to 6.66 GBq demonstrated an adverse linear dose-response association between RAI and risk of CVD [RR per 1 GBq, 0.98 (95% CI: 0.95–1.01)] with no evidence for departure from linearity (Wald test, P = 0.2). Figure 3B was non-linear associated model [RR per 1 GBq, 0.94 (95% CI: 0.78–1.32), P = 0.52]. The findings demonstrated no beneficial nor harmful effect on CVD among different RAI doses.

Dose-response association between RAI dose and the risk of CVD: (A) linearity risk ratio (RR) per 1 GBq, 0.98 [95% CI: 0.95–1.01], P = 0.20; (B) non-linearity RR per 1 GBq, 0.94 [95% CI: 0.78–1.32], P = 0.52.

 Association between levothyroxine dose or TSH level and the risk for CVD or CVD mortality

Systematic review of the association between CVD risk and different dosages of levothyroxine is summarized in Table 1. Both the risk for CAD and ischemic stroke were increased in TC patients treated with gradually higher dosages of levothyroxine after thyroidectomy. In addition, each 10-fold decrease in geometric mean TSH level could significantly predict CVD mortality, with an HR of 3.08 (95% CI: 1.32‒7.21) after adjusted, but not all-cause mortality.

 Publication bias, study heterogeneity, and meta-regression

The risk of publication bias was found to be non-significant for studies addressing CAD, cerebrovascular disease, Af, and CVD mortality (Supplementary Figure S1). Meta-regression analysis demonstrated no statistically significant association between risk for CAD, cerebrovascular disease, Af and CVD mortality and mean age, women proportion, and follow up years (Table 2).

Meta-regression for the association between baseline characteristics, including mean age, the proportion of women, and follow up years, and the risk of (A) CAD; (B) cerebrovascular disease; (C) Af; (D) CVD mortality among patients with TC compared with general health population.

Slope 95% CI τ2 (%) I2 (%) R2 (%) p value
Coronary artery diseases
 Age −0.01 −0.08 0.05 0.93 66.28 0 0.57
 The proportion of women 0.01 −0.03 0.05 0.84 60.93 0 0.44
 Follow up years −0.01 −0.04 0.02 0.13 25.27 73.45 0.23
Cerebrovascular diseases
 Age −0.02 −0.05 0.01 0.11 15.39 82.18 0.15
 The proportion of women 0.005 −0.04 0.05 0.86 57.73 0 0.71
 Follow up years −0.01 −0.05 0.03 0.1 15.98 0 0.33
Atrial fibrillation
 Age −0.01 −0.06 0.03 1.23 64.01 0 0.58
 The proportion of women −0.003 −0.03 0.03 12.15 68.64 0 0.83
 Follow up years −0.01 −0.04 0.02 1.12 69.64 6.32 0.45
CVD mortality
 Age −0.06 −0.36 0.24 38.52 99.25 0 0.63
 The proportion of women −0.2 −0.47 0.06 23.06 98.67 30 0.11
 Follow up years 0.02 −0.13 0.18 41.36 99.27 0 0.72
Discussion

The present study showed that TC patients were prone to experience cerebrovascular disease and Af. The incidence of CAD and CVD mortality among TC patients did not appear to be different from the general healthy population. In addition, there was no significant association between RAI and CVD in patients with TC. However, according to limited evidence, lenvatinib may increase CVD risk.

3,822 patients from Utah Population Database (UPDB) demonstrated that male, overweight or obese, older at cancer diagnosis, TSH suppression therapy, distant metastases at cancer diagnosis, and a higher Charlson comorbidity index score were associated with an increased CVD risk among TC survivors (34). In our study, majority of patients were women and the mean age was between 40 and 50 years old. Both Izkhakov et al. (35) and Suh et al. (28) demonstrated a significantly increased CAD risk in patients with TC compared with the general healthy population. Pajamaki et al. (17) and Toulis et al. (29) showed no significant risk of CAD, but the population number of these two studies were smaller than the former two studies. Our study demonstrated a neutral risk of CAD in the random effect model, which was inconsistent with previous meta-analysis (36). However, in the common effect model, our study demonstrated a significantly higher risk of CAD. The difference was that we also included Zoltek's study (19), despite this study using standardized incidence ratios as the statistical strategy. Toulis et al. (29), Izkhakov et al. (35), and Suh et al. (28) reported a significantly higher risk of cerebrovascular disease, while Blackburn et al. (27) and Pajamaki et al. (17) showed no significant risk of cerebrovascular disease. The former three studies had higher population number than the latter two studies. Our study showed a significantly higher risk for cerebrovascular disease, which was consistent with previous meta-analysis (36). However, the hazard ratio that previous meta-analysis extracted from Toulis's study (29) was unadjusted. In addition, we included Blackburn's study (27). Among all the studies above, only Izkhakov et al. (35) included patients with preexisting CVD, while the others excluded patients with preexisting CVD. Besides, the proportion of CVD in placebo group was much higher than TC group in Izkhakov's study (8.2% vs. 3%) (35). Regarding Af, Hesselink et al. (31), Pajamäki et al. (17), Suh et al. (28) and Toulis et al. (29) indicated that the risk tended to increase among patients with TC; however, Blackburn et al. (27) could not find the difference. Only Hesselink's study (31) included patients with preexisting CVD, with higher proportion of CVD in placebo group than TC group (1.6% vs. 1.2%). Our result was consistent with another meta-analysis (37), which also indicated a significantly higher risk of Af. However, we excluded Abonowara's (38) study since this was a cross-sectional study rather than a cohort study.

The pathophysiological mechanism of increased cerebrovascular disease in patients with TC remains unclear. Suh et. al found a low incidence of Af in patients who developed ischemic stroke, which may suggest that Af is not a primary factor associated with ischemic stroke (28). Both alternatives of thyroid function, such as subclinical hyperthyroidism and hypothyroidism, could be possible reasons explaining the increased risk for CVD in patients with TC. For example, research had shown that subclinical hyperthyroidism increased left ventricular size (39, 40), systolic hypertension, diastolic dysfunction and reduce arterial elasticity (41). In addition, the pro-thrombotic effects related to subclinical hyperthyroidism have been reported to be involved in the development of hypercoagulability (38, 42–45). In contrast, hypothyroidism has also been linked to oxidation of low-density lipoprotein, induction of atherosclerosis, and consequent diastolic hypertension (46, 47). Finally, dysrhythmia (48–50), angina (48–50) and coronary heart disease (46, 47) during TC treatment may possibly contribute to the increased odds for CVD. Regarding TSH-suppression therapy and CVD incidence, a U-shaped relationship between either TSH concentration or cumulative dose of levothyroxine and CVD risk was observed (17, 28). Higher odds for CVD were noted in the end range of TSH-suppression therapy. Hesselink et al. (18) described the detrimental effect of 10-fold TSH level decreasing on CVD mortality, while there was still lack of evidence supporting the effect of TSH level on Af (31, 33). The discrepancy in results between these cohorts could be explained by different statistical methods, end points, and data acquisition methods.

Further investigations of CVD mortality rate demonstrated no difference after follow up of 4,082 patients with TC for 3 years (51). Pajamäki et al. (17) (901 patients follow up for 18.8 years) and Lu et al. (16) (30,778 patients follow up for 5.67 years) showed significantly lower risk of CVD mortality. In contrast to these studies, Hesselink et al. (18) studied 524 patients with 10.5 follow-up years and noted that CVD mortality risk increased after adjusting for cardiovascular risk factors. Higher proportion of CVD at baseline in placebo group than TC group was noted in Hesselink (18) and Lu's (16) studies. Whether the difference was owing to different CVD surveillance strategy was unknown. Our study suggested neutral risk of CVD mortality in patients with TC. Previous research suggested that RAI may trigger increased short-term intima media thickness in the arteries (52) or echocardiographic variability (53). A previous epidemiological cohort study investigating hyperthyroidism demonstrated that, after undergoing RAI treatment, the subsequent incidence of CVD may increase (54–57). However, other studies indicated that patients with TC who underwent RAI treatment had non-significant odds (range, 0.71‒1.29) for developing CVD compared with those without RAI (27, 51). Our meta-analysis revealed that TC patients receiving RAI treatment was not associated with a higher risk for CVD. The association between RAI dose and CVD incidence is controversial. One study suggested that the cumulative dose of RAI was associated with a gradually increased risk for Af (31). However, other studies failed to find an association between higher risk for stroke and RAI dose (24, 25). Our study revealed that there was no beneficial nor harmful effect among different RAI doses. The pathogenic mechanism between RAI treatment and CVD is also inconclusive. The major explanation of the discrepancies of CVD incidence with RAI therapy between patients with hyperthyroidism and TC may be that the underlying hyperthyroidism-related cardiotoxic effects may not be fully reversed even after restoring euthyroidism (55). On the other hand, a study showed that iodine-131 reduced cell proliferation and induced apoptosis of human cardiac muscle cells through the p53/Bax/caspase-3 and PIDD/caspase-2/t-BID/cytochrome c/caspase-3 signaling pathway (58). Since there is still lack of evidence, whether higher risk of CVD mortality in Hesselink's study (18) is due to higher RAI dose (200 mCi) than other studies (100–120 mCi) still warrant further research.

Tyrosine kinase inhibitors (TKI) has become the final treatment option for metastatic TC that is refractory to surgery or RAI, to improve the prognosis of patients with distant metastasis and progressive disease (59). According to previous literature, TKI is associated with cardiotoxicity (60). Cardiotoxicity may manifest as hypertension, heart failure, cardiac arrhythmias, thromboembolic events, fluid retention, or exacerbation of CAD. One RCT revealed a significantly increased risk of lenvatinib for CVD [RR 3.54 (95% CI: 1.03‒12.13)] (13). Nonetheless, the association between TKI and thyroid cancer still warrant further research.

Our meta-regression analysis demonstrated no statistically significant association between risk for CAD, cerebrovascular disease, Af and CVD mortality and mean age, women proportion, and follow up years. Whether age and sex effect the development of CVD in patients with TC remains unclear. A cohort study from UPDB revealed that TC survivors diagnosed at <40 years have an increased risk for several circulatory conditions when compared with the matched cancer-free population (27). Both patients with age < 40 or age ≥ 40 had increased risk for heart disease 1 to 10 years after cancer diagnosis (27). Only hypertension remained significant across 1 to >10 years after cancer diagnosis in both age groups, while diseases of the circulatory system remained significantly increased across 1 to >10 years for patients with age ≥ 40 (27). The association between TC and CVD in younger patients may be due to more RAI treatment (61–64) and TSH suppression therapy (65). TC survivors have been reported to have increased rates of distress and worry, especially in younger survivors (66, 67), which may contribute to the development of hypertension. A retrospective analysis from the SEER database indicated that male patients had poorer overall and cancer-specific survival (16). Male patients with TC had a larger tumor size and a larger proportion of metastasis, while female patients had a higher incidence and earlier age at diagnosis with TC (48.0 vs. 52.5 years old) (16). The better prognosis of TC in women is limited to the time of reproductive activity (68–70). Taken together, early detection of cardiovascular adverse effects in patients with TC appears to be justified in attempts to prevent CVD-related complications and mortality. The effect on CVD among different RAI dosage, levothyroxine dosage, TSH level, cancer stage and histology type still call for further research.

Our study has two advantages over prior meta-analyses. First, we included more qualified cohort studies. We also included RCTs due to lack of cohort studies. Second, the present study is the first meta-analysis to investigate the relationship between TC and RAI or lenvatinib. However, the evidence is still scarce. On the other hand, the present study had several limitations, the first of which was the limited number of eligible studies. Despite efforts to search using specific keywords to retrieve all relevant articles, the number of included studies was small. Further studies investigating the association between TC and CVD are needed to further optimize risk identification. Second, the heterogeneity of exposure measurement, end point ascertainment, statistical analysis (including cox proportional hazards model, standardized incidence ratio, and standardized mortality ratio), and data acquisition methods reduced our ability to compare the studies with one another. Pooled estimates could not be calculated on part of studies due to insufficient data. Future investigations are still needed to explore the potential causal pathways between exposure and outcome. Third, some of the studies lacked information of cancer parameters, such as cytology, staging, or TSH concentrations. Further understanding of the effects of treatment for TC on the cardiovascular system can be improved by stratifying detailed cancer information into covariates in future research. Fourth, despite the subgroups of each study were not overlapped, each of the subgroup was compared with the same control group to evaluate the risk for CVD. Finally, the meta-analysis could not exclude unmeasured residual confounders because most of the included evidence was derived from observational studies. However, the odds in these studies were adjusted for multiple relevant confounders to eliminate potential bias.

 Conclusion

TC was significantly associated with a higher risk for cerebrovascular disease and Af, although the hazard risk was not different between patients who did and did not undergo RAI ablation. Lenvatinib may increase CVD risk according to limited evidence. These results provide insights toward optimizing TC strategies that should consider the potential harms and benefits on cardiovascular health during cancer treatment.

 Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

 Ethics statement

The studies involving human participants were reviewed and approved by The Mackay Memorial Hospital Committee Review Board approved the study protocol (IRB 20MMHIS475e approved with exempt review). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

 Author contributions

W-HT, P-JT and M-CT: write the main manuscript text. W-HT, Y-HZ and M-CT: literature review and data extraction. M-CT and S-CL: data analysis. M-CT, M-NC and S-PC: conceptualization. C-CL and K-LC: supervision. All authors contributed to the article and approved the submitted version.

 Funding

This paper was supported by grants from the Ministry of Science and Technology (MOST 110-2314-B-195-004).

 Acknowledgments

The authors appreciate the cooperation of Taiwan Cancer Registry Center and Ministry of Science and Technology (MOST 110-2314-B-195-004) for supporting this study.

 Conflict of interest

The reviewer YWW declared a past co-authorship with the author KLC to the handling editor. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

 Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcvm.2023.1075844/full#supplementary-material.

 References BrayFFerlayJSoerjomataramISiegelRLTorreLAJemalA. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. (2018) 68(6):394–424. 10.3322/caac.2149230207593 La VecchiaCMalvezziMBosettiCGaravelloWBertuccioPLeviF Thyroid cancer mortality and incidence: a global overview. Int J Cancer. (2015) 136(9):2187–95. 10.1002/ijc.2925125284703 RahibLSmithBDAizenbergRRosenzweigABFleshmanJMMatrisianLM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. (2014) 74(11):2913–21. 10.1158/0008-5472.CAN-14-015524840647 HundahlSAFlemingIDFremgenAMMenckHR. A national cancer data base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995 [see commetns]. Cancer. (1998) 83(12):2638–48. 10.1002/(SICI)1097-0142(19981215)83:12%3C2638::AID-CNCR31%3E3.0.CO;2-19874472 HaugenBRAlexanderEKBibleKCDohertyGMMandelSJNikiforovYE 2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American thyroid association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid. (2016) 26(1):1–133. 10.1089/thy.2015.002026462967 LeboulleuxSBournaudCChougnetCNZerdoudSAl GhuzlanACatargiB Thyroidectomy without radioiodine in patients with low-risk thyroid cancer. N Engl J Med. (2022) 386(10):923–32. 10.1056/NEJMoa211195335263518 SutherlandRTsangVClifton-BlighRJGildML. Papillary thyroid microcarcinoma: is active surveillance always enough? Clin Endocrinol (Oxf). (2021) 95(6):811–7. 10.1111/cen.1452934021503 GiordanoDGradoniPOrettiGMolinaEFerriT. Treatment and prognostic factors of papillary thyroid microcarcinoma. Clin Otolaryngol. (2010) 35(2):118–24. 10.1111/j.1749-4486.2010.02085.x20500581 AroraNTurbendianHKKatoMAMooTAZarnegarRFaheyTJ3rd. Papillary thyroid carcinoma and microcarcinoma: is there a need to distinguish the two? Thyroid. (2009) 19(5):473–7. 10.1089/thy.2008.018519348582 HayIDHutchinsonMEGonzalez-LosadaTMcIverBReinaldaMEGrantCS Papillary thyroid microcarcinoma: a study of 900 cases observed in a 60-year period. Surgery. (2008) 144(6):980–7; discussion 7–8. 10.1016/j.surg.2008.08.03519041007 CreachKMSiegelBANussenbaumBGrigsbyPW. Radioactive iodine therapy decreases recurrence in thyroid papillary microcarcinoma. ISRN Endocrinol. (2012) 2012:816386. 10.5402/2012/81638622462017 AraqueKAGubbiSKlubo-GwiezdzinskaJ. Updates on the management of thyroid cancer. Horm Metab Res. (2020) 52(8):562–77. 10.1055/a-1089-787032040962 SchlumbergerMTaharaMWirthLJRobinsonBBroseMSEliseiR Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. (2015) 372(7):621–30. 10.1056/NEJMoa140647025671254 BroseMSNuttingCMJarzabBEliseiRSienaSBastholtL Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. (2014) 384(9940):319–28. 10.1016/S0140-6736(14)60421-924768112 DuBWangFWuLWangZZhangDHuangZ Cause-specific mortality after diagnosis of thyroid cancer: a large population-based study. Endocrine. (2021) 72(1):179–89. 10.1007/s12020-020-02445-832770440 LuYLLinSFWuMHLeeYYLeePWChangSH Survival and death causes in thyroid cancer in Taiwan: a nationwide case-control cohort study. Cancers (Basel). (2021) 13(16):3955. 10.3390/cancers13163955 PajamäkiNMetsoSHakalaTEbelingTHuhtalaHRyödiE Long-term cardiovascular morbidity and mortality in patients treated for differentiated thyroid cancer. Clin Endocrinol (Oxf). (2018) 88(2):303–10. 10.1111/cen.13519 Hesselink ENKHesselink MSKde BockGHGansevoortRTBakkerSJVredeveldEJ Long-term cardiovascular mortality in patients with differentiated thyroid carcinoma: an observational study. J Clin Oncol. (2013) 31(32):4046–53. 10.1200/JCO.2013.49.104324101052 ZoltekMAnderssonTMHedmanCIhre-LundgrenCNordenvallC. Cardiovascular incidence in 6900 patients with differentiated thyroid cancer: a Swedish nationwide study. World J Surg. (2020) 44(2):436–41. 10.1007/s00268-019-05249-831659412 LiberatiAAltmanDGTetzlaffJMulrowCGøtzschePCIoannidisJP The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. Br Med J (Clin Res Ed). (2009) 339:b2700. 10.1136/bmj.b2700 MorganRLWhaleyPThayerKASchünemannHJ. Identifying the PECO: a framework for formulating good questions to explore the association of environmental and other exposures with health outcomes. Environ Int. (2018) 121(Pt 1):1027–31. 10.1016/j.envint.2018.07.01530166065 BeroLChartresNDiongJFabbriAGhersiDLamJ The risk of bias in observational studies of exposures (ROBINS-E) tool: concerns arising from application to observational studies of exposures. Syst Rev. (2018) 7(1):242. 10.1186/s13643-018-0915-230577874 GreenlandSLongneckerMP. Methods for trend estimation from summarized dose-response data, with applications to meta-analysis. Am J Epidemiol. (1992) 135(11):1301–9. 10.1093/oxfordjournals.aje.a1162371626547 LinCYLinCLLoYCKaoCH. Association between radioiodine treatment for thyroid cancer and risk of stroke. Head Neck. (2017) 39(11):2311–8. 10.1002/hed.2490328815788 KimKJSongJEKimJYBaeJHKimNHYooHJ Effects of radioactive iodine treatment on cardiovascular disease in thyroid cancer patients: a nationwide cohort study. Ann Transl Med. (2020) 8(19):1235. 10.21037/atm-20-522233178767 DiscacciatiACrippaAOrsiniN. Goodness of fit tools for dose-response meta-analysis of binary outcomes. Res Synth Methods. (2017) 8(2):149–60. 10.1002/jrsm.119426679736 BlackburnBEGanzPARoweKSnyderJWanYDeshmukhV Aging-Related disease risks among young thyroid cancer survivors. Cancer Epidemiol Biomarkers Prev. (2017) 26(12):1695–704. 10.1158/1055-9965.EPI-17-062329167277 SuhBShinDWParkYLimHYunJMSongSO Increased cardiovascular risk in thyroid cancer patients taking levothyroxine: a nationwide cohort study in Korea. Eur J Endocrinol. (2019) 180(1):11–20. 10.1530/EJE-18-055130400044 ToulisKAViolaDGkoutosGKeerthyDBoelaertKNirantharakumarK. Risk of incident circulatory disease in patients treated for differentiated thyroid carcinoma with no history of cardiovascular disease. Clin Endocrinol (Oxf). (2019) 91(2):323–30. 10.1111/cen.1399030993728 IzkhakovEMeyerovitchJBarchanaMShachamYSternNKeinan-BokerL. Long-term cardiovascular and cerebrovascular morbidity in Israeli thyroid cancer survivors. Endocr Connect. (2019) 8(4):398–406. 10.1530/EC-19-003830865929 Klein HesselinkENLefrandtJDSchuurmansEPBurgerhofJGGroenBGansevoortRT Increased risk of atrial fibrillation after treatment for differentiated thyroid carcinoma. J Clin Endocrinol Metab. (2015) 100(12):4563–9. 10.1210/jc.2015-278226480284 KaoCHChungCHChienWCShenDHLinLFChiuCH Radioactive iodine treatment and the risk of long-term cardiovascular morbidity and mortality in thyroid cancer patients: a nationwide cohort study. J Clin Med. (2021) 10(17):4032. 10.3390/jcm10174032. WangLYSmithAWPalmerFLTuttleRMMahrousANixonIJ Thyrotropin suppression increases the risk of osteoporosis without decreasing recurrence in ATA low- and intermediate-risk patients with differentiated thyroid carcinoma. Thyroid. (2015) 25(3):300–7. 10.1089/thy.2014.028725386760 ParkJBlackburnBEGanzPARoweKSnyderJWanY Risk factors for cardiovascular disease among thyroid cancer survivors: findings from the Utah cancer survivors study. J Clin Endocrinol Metab. (2018) 103(7):2468–77. 10.1210/jc.2017-0262929850817 IzkhakovEKeinan-BokerLBarchanaMShachamYYaishICarmel NeidermanNN Long-term all-cause mortality and its association with cardiovascular risk factors in thyroid cancer survivors: an Israeli population-based study. BMC Cancer. (2020) 20(1):892. 10.1186/s12885-020-07401-332942995 LeeEKAhnHYKuEJYooWSLeeYKNamKH Cardiovascular outcomes in thyroid cancer patients treated with thyroidectomy: a meta-analysis. J Clin Endocrinol Metab. (2021) 106(12):3644–54. 10.1210/clinem/djab57634347085 KostopoulosGDoundoulakisIAntzaCBourasENirantharakumarKTsiachrisD Incident atrial fibrillation in patients with differentiated thyroid cancer: a meta-analysis. Endocr Relat Cancer. (2021) 28(5):325–35. 10.1530/ERC-20-049633794503 AbonowaraAQuraishiASappJLAlqambarMHSaricAO'ConnellCM Prevalence of atrial fibrillation in patients taking TSH suppression therapy for management of thyroid cancer. Clin Invest Med. (2012) 35(3):E152–6. 10.25011/cim.v35i3.1659122673318 BiondiBPalmieriEALombardiGFazioS. Effects of thyroid hormone on cardiac function: the relative importance of heart rate, loading conditions, and myocardial contractility in the regulation of cardiac performance in human hyperthyroidism. J Clin Endocrinol Metab. (2002) 87(3):968–74. 10.1210/jcem.87.3.830211889145 BiondiBPalmieriEAFazioSCoscoCNoceraMSaccàL Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J Clin Endocrinol Metab. (2000) 85(12):4701–5. 10.1210/jcem.85.12.708511134131 BoswijkESandersKJCBroedersEPMde LigtMVijgenGHavekesB TSH Suppression aggravates arterial inflammation - an (18)F-FDG PET study in thyroid carcinoma patients. Eur J Nucl Med Mol Imaging. (2019) 46(7):1428–38. 10.1007/s00259-019-04292-w30859432 AbdulrahmanRMDelgadoVHoftijzerHCNgACEweSHMarsanNA Both exogenous subclinical hyperthyroidism and short-term overt hypothyroidism affect myocardial strain in patients with differentiated thyroid carcinoma. Thyroid. (2011) 21(5):471–6. 10.1089/thy.2010.031921417919 SmitJWEustatia-RuttenCFCorssmitEPPereiraAMFrölichMBleekerGB Reversible diastolic dysfunction after long-term exogenous subclinical hyperthyroidism: a randomized, placebo-controlled study. J Clin Endocrinol Metab. (2005) 90(11):6041–7. 10.1210/jc.2005-062016131580 ShargorodskyMSerovSGavishDLeibovitzEHarpazDZimlichmanR. Long-term thyrotropin-suppressive therapy with levothyroxine impairs small and large artery elasticity and increases left ventricular mass in patients with thyroid carcinoma. Thyroid. (2006) 16(4):381–6. 10.1089/thy.2006.16.38116646685 HorneMK3rdSinghKKRosenfeldKGWesleyRSkarulisMCMerrymanPK Is thyroid hormone suppression therapy prothrombotic? J Clin Endocrinol Metab. (2004) 89(9):4469–73. 10.1210/jc.2004-053615356049 SundaramVHannaANKoneruLNewmanHAFalkoJM. Both hypothyroidism and hyperthyroidism enhance low density lipoprotein oxidation. J Clin Endocrinol Metab. (1997) 82(10):3421–4. 10.1210/jcem.82.10.43159329379 SheuJJKangJHLinHCLinHC. Hyperthyroidism and risk of ischemic stroke in young adults: a 5-year follow-up study. Stroke. (2010) 41(5):961–6. 10.1161/STROKEAHA.109.57774220360542 BiondiBFilettiSSchlumbergerM. Thyroid-hormone therapy and thyroid cancer: a reassessment. Nat Clin Pract Endocrinol Metab. (2005) 1(1):32–40. 10.1038/ncpendmet002016929364 ColletTHGusseklooJBauerDCden ElzenWPCappolaARBalmerP Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med. (2012) 172(10):799–809. 10.1001/archinternmed.2012.40222529182 SugitaniIFujimotoY. Effect of postoperative thyrotropin suppressive therapy on bone mineral density in patients with papillary thyroid carcinoma: a prospective controlled study. Surgery. (2011) 150(6):1250–7. 10.1016/j.surg.2011.09.01322136848 KimKJJangSKimKJAnJHKimNHShinDY Actual causes of death in thyroid cancer patients in Korea: a nationwide case control cohort study. Eur J Endocrinol. (2020) 182(1):103–10. 10.1530/EJE-19-054831721722 SürücüEBekişRSengözTDemirYCelikAOOrbayO The effect of radioiodine on the intima media thickness of the carotid artery. Mol Imaging Radionucl Ther. (2013) 22(3):85–9. 10.4274/Mirt.24119 WeichselbaumRCFeeneyDAJessenCR. Relationship between selected echocardiographic variables before and after radioiodine treatment in 91 hyperthyroid cats. Vet Radiol Ultrasound. (2005) 46(6):506–13. 10.1111/j.1740-8261.2005.00099.x16396269 FranklynJAMaisonneuvePSheppardMCBetteridgeJBoyleP. Mortality after the treatment of hyperthyroidism with radioactive iodine. N Engl J Med. (1998) 338(11):712–8. 10.1056/NEJM1998031233811039494147 MetsoSJaatinenPHuhtalaHAuvinenAOksalaHSalmiJ. Increased cardiovascular and cancer mortality after radioiodine treatment for hyperthyroidism. J Clin Endocrinol Metab. (2007) 92(6):2190–6. 10.1210/jc.2006-232117374710 MetsoSAuvinenASalmiJHuhtalaHJaatinenP. Increased long-term cardiovascular morbidity among patients treated with radioactive iodine for hyperthyroidism. Clin Endocrinol (Oxf). (2008) 68(3):450–7. 10.1111/j.1365-2265.2007.03064.x17941909 RyödiESalmiJJaatinenPHuhtalaHSaaristoRVälimäkiM Cardiovascular morbidity and mortality in surgically treated hyperthyroidism - a nation-wide cohort study with a long-term follow-up. Clin Endocrinol (Oxf). (2014) 80(5):743–50. 10.1111/cen.12359 WangYLiuCWangJZhangYChenL. Iodine-131 induces apoptosis in human cardiac muscle cells through the p53/bax/caspase-3 and PIDD/caspase-2/t-BID/cytochrome c/caspase-3 signaling pathway. Oncol Rep. (2017) 38(3):1579–86. 10.3892/or.2017.581328714021 CuomoFGianiCCobellisG. The role of the kinase inhibitors in thyroid cancers. Pharmaceutics. (2022) 14(5):1040. 10.3390/pharmaceutics1405104035631627 Grela-WojewodaAPacholczak-MadejRAdamczykAKormanMPüsküllüoğluM. Cardiotoxicity induced by protein kinase inhibitors in patients with cancer. Int J Mol Sci. (2022) 23(5):2815. 10.3390/ijms2305281535269958 Fard-EsfahaniAEmami-ArdekaniAFallahiBFard-EsfahaniPBeikiDHassanzadeh-RadA Adverse effects of radioactive iodine-131 treatment for differentiated thyroid carcinoma. Nucl Med Commun. (2014) 35(8):808–17. 10.1097/MNM.000000000000013224751702 JeongSYKimHWLeeSWAhnBCLeeJ. Salivary gland function 5 years after radioactive iodine ablation in patients with differentiated thyroid cancer: direct comparison of pre- and postablation scintigraphies and their relation to xerostomia symptoms. Thyroid. (2013) 23(5):609–16. 10.1089/thy.2012.010623153322 WuJXYoungSRoKLiNLeungAMChiuHK Reproductive outcomes and nononcologic complications after radioactive iodine ablation for well-differentiated thyroid cancer. Thyroid. (2015) 25(1):133–8. 10.1089/thy.2014.034325289542 McLeodDSSawkaAMCooperDS. Controversies in primary treatment of low-risk papillary thyroid cancer. Lancet (London, England). (2013) 381(9871):1046–57. 10.1016/S0140-6736(12)62205-323668555 BiondiBCooperDS. Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer. Thyroid. (2010) 20(2):135–46. 10.1089/thy.2009.031120151821 RoerinkSHde RidderMPrinsJHuijbersAde WiltHJMarresH High level of distress in long-term survivors of thyroid carcinoma: results of rapid screening using the distress thermometer. Acta Oncologica (Stockholm, Sweden). (2013) 52(1):128–37. 10.3109/0284186X.2012.72382223101467 BresnerLBanachRRodinGThabaneLEzzatSSawkaAM. Cancer-related worry in Canadian thyroid cancer survivors. J Clin Endocrinol Metab. (2015) 100(3):977–85. 10.1210/jc.2014-316925393643 JonklaasJNogueras-GonzalezGMunsellMLitofskyDAinKBBigosST The impact of age and gender on papillary thyroid cancer survival. J Clin Endocrinol Metab. (2012) 97(6):E878–87. 10.1210/jc.2011-286422496497 ZahediABondazLRajaramanMLeslieWDJeffordCYoungJE Risk for thyroid cancer recurrence is higher in men than in women independent of disease stage at presentation. Thyroid. (2020) 30(6):871–7. 10.1089/thy.2018.077531524071 ZhangDTangJKongDCuiQWangKGongY Impact of gender and age on the prognosis of differentiated thyroid carcinoma: a retrospective analysis based on SEER. Horm Cancer. (2018) 9(5):361–70. 10.1007/s12672-018-0340-y30014218