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Page 4 of 8 Izkhakov et al. J Cancer Metastasis Treat 2021;7:24 https://dx.doi.org/10.20517/2394-4722.2021.24

levothyroxine was high. Specifically, TC survivors who received < 115, 115-144, 145-169 and > 170 µg/day
presented with an increased risk of AF (adjusted HR = 1.43 [1.27-1.62], 1.41 [1.26-1.58], 1.66 [1.49-1.85],
[29]
and 1.78 [1.6-1.98], respectively). Zoltek et al. reported a 2-fold higher hospitalization rate for AF among
6900 DTC survivors compared to the general Swedish population during the first 5 surveillance years, and
an increased AF rate of ~2-2.5 fold among DTC patients aged 54 years or less.

Cerebrovascular morbidity
Suh et al. investigated cardiovascular morbidity as well as the incidence of ischemic stroke. TC survivors
[27]
had an elevated risk of ischemic stroke (HR = 1.15 [1.09-1.22]) which was more prominent in the group of
TC survivors who were treated with levothyroxine at a dosage of 170 µg/day or more (HR = 1.56 [1.42-
1.72]).

Izkhakov et al. also assessed cerebrovascular outcome among DTC survivors and found an independent
[28]
risk factor of new cerebrovascular events (HR = 1.19 [1.04-1.37]) compared to matched controls. The
increased risk for new cerebrovascular event remained high (HR = 1.16 [1.01-1.36]) after those with a
history of cardiovascular and cerebrovascular events were excluded.

Zoltek et al. reported a higher hospitalization rate for cerebrovascular disease (SIR = 1.2, 95%CI: 1.04-
[29]
1.38) among female DTC survivors. Toulis et al. assessed the potential cardiovascular effect of exogenous
[32]
hyperthyroidism among 3009 British DTC survivors with no cardiovascular disease and 11,303 matched
controls. After a median 5-year follow-up, no difference was found in the risk of ischemic heart disease,
although the risk of AF and stroke was higher among the DTC survivors compared to the controls (HR =
1.71 [1.36-2.15] and 1.34 [1.05-1.72], respectively). These findings warrant periodic screening for AF among
TSH-suppressed DTC survivors.

Associations between potential cardiovascular risk factors and cardiovascular/cerebrovascular
morbidity among TC survivors
Several pathological and high-risk conditions have been found among individuals with TC in comparison to
the healthy controls. Park et al. investigated the relationship of potential risk factors and treatment effects
[33]
with cardiovascular disease outcome among 3822 TC survivors, using the state-wide Utah Population
Database during a mean 8.4-year follow-up. They found a significant association between the following
factors and a high risk of cardiovascular conditions: age at diagnosis (40-65 years, HR = 1.66 [1.46-1.88]; and
> 65 years, HR = 2.84 [2.46-3.27], compared to < 40 years), male sex (compared to female sex, HR = 1.46
[1.31-1.62]), TSH suppression therapy (compared to no therapy, HR = 1.25 [1.12-1.4]), overweight and
obesity (compared to normal BMI, HR = 1.24 [1.11-1.39] and 1.41 [1.25-1.6], respectively), the presence of
any comorbidity (compared to none, HR = 4.47 [3.87-5.15]), and TC distant metastasis (compared to
localized TC, HR = 1.35 [1.03-1.77]).

Izkhakov et al. likewise reported an elevated risk for cardiovascular morbidity among DTC survivors aged
[28]
55-64 (HR = 1.29 [1.08-1.53]) and 65-74 years (HR = 1.36 [1.14-1.61]) compared to matched controls. The
increased risk in those age groups persisted after individuals with past cardiovascular events were excluded
(HR = 1.32 [1.09-1.60] and 1.41 [1.16-1.72], respectively). In addition, there was an association between low
free thyroxin 3 (FT3) and low FT4 levels at baseline and elevated risk for new atherosclerotic cardiovascular
events at the end of the study (HR = 1.38 [1.16-1.64] and 1.02 [1.01-1.04], respectively). The FT3/FT4 ratio
at baseline showed a trend of an inverse correlation with new atherosclerotic cardiovascular events (P =
0.067).