Mildly Elevated Thyroxine Levels Linked to Sudden Cardiac Death

Patrice Wendling

September 14, 2016

ROTTERDAM, THE NETHERLANDS — Higher free thyroxine (FT4) levels are associated with an increased risk of sudden cardiac death (SCD), a large population-based study finds[1].

The absolute 10-year risks of SCD increased from 1% for patients with low-normal FT4 levels to 4% for those with high-normal FT4 levels.

Lead author Dr Layal Chaker (Erasmus University Medical School, Rotterdam, the Netherlands) explained to heartwire from Medscape that this is an entirely novel finding, although several studies have shown an association between thyroid function and cardiovascular disease.

"We did not know that sudden cardiac death was related to thyroid function, and I think it's important as well to realize that it seems to be independent of cardiovascular risk factors," she said.

SCD accounts for more than half of CV deaths and 15% to 20% of total mortality. Chaker noted that the predictability of SCD in the general population is poor because almost half of SCD cases are the first sign of cardiac disease.

Only about 3% of participants were on levothyroxine thyroid hormone replacement therapy, so it wasn't possible to determine whether their risk is similar to endogenous thyroid hormone. Still, "We know that only about 60% [of patients] are in the right range, so that means there are people being over- and undertreated. So I think our results caution against the people who are being overtreated," she said.

Rotterdam Study

The study, published September 6, 2016 in Circulation, used data from three independent cohorts within the prospective Rotterdam Study to identify 10,318 participants >45 years old (mean 64.7 years; 57% female) with baseline serum thyroid-stimulating hormone (TSH) and FT4 measurements. The normal range for TSH was defined as 0.4 to 4.0 mIU/L, and the reference range for FT4 as 0.85 to 1.95 ng/dL (11-25 pmol/L).

A total of 261 SCD events occurred during a maximum follow-up of 21.2 years, for an incidence rate of 3.1 per 1000 person-years.

Results show that the fully adjusted risk of SCD was 2.26 higher in participants who were euthyroid (TSH 0.4–4.0 mIU/L). As expected, because of its inverse relationship with FT4, higher TSH levels were associated with a concomitant lower risk of SCD.

Thyroid Function and Risk of SCD

Thyroid function measurement SCD events Total participants Adjusted HR* (95%CI)
Full range of measurement
TSH, mIU/L 261 10314 0.92 (0.80–1.04)
FT4, ng/dL 249 10225 1.77 (1.09–2.86)
Euthyroid participants
TSH, mIU/L 231 8953 0.80 (0.62–1.04)
FT4, ng/dL 222 8881 2.26 (1.30–3.94)
*Model adjusted for sex, age, cohort, pulse rate, hypertension, cholesterol, diabetes mellitus, body mass index, smoking, and QT interval

Caution Called for

Even though the association with FT4 and SCD seems quite strong, Chaker said the results need to be replicated and risk-prediction studies conducted to determine whether "thyroid hormone really adds so much next to the cardiovascular risk factors that we can really use it."

She noted that the limitations of the study are possible residual confounding; the availability of only one baseline thyroid measurement, which does not allow for temporal changes in TSH and FT4; and generalizability of the results, which may not be applicable to other populations because nearly all participants were white.

Dr Fabio Monzani (University of Pisa, Italy) commented to heartwire in an email that the identification of additional risk factors for SCD is important but said no conclusions can be drawn on the benefits or risks of thyroid medication in cardiac patients.

He pointed out that previous data[2] from the investigators showed an increased risk of atrial fibrillation with higher FT4 levels within the normal range, especially in younger persons, but at the opposite corner of the topic, two other studies[3,4] suggest that decreased thyroid function may represent a protective condition in healthy aging.

"In this setting, physicians might be encouraged to undertreat low thyroid function in cardiac patients by using FT4 levels as a possible screening tool for assessing SCD risk," Monzani said. "However, as correctly stated by the authors, thyroid-hormone levels are regulated by the hypothalamic-pituitary-thyroid axis, which has a unique set-point for each individual, and a wide variety of factors can modulate the set-point, including illness and aging."

Endocrinologist Dr John Walsh (University of Western Australia, Crawley) told heartwire in an email that the findings advance clinical understanding but are unlikely to affect patient management.

"There is already a lot of evidence that subclinical hypothyroidism in older people does not increase the risk of CVD. This is another piece of evidence to support not treating subclinical hypothyroidism in older people who are otherwise well and asymptomatic," he said.

Chaker is supported by grants from the Netherlands Organization for Health Research and Development and Erasmus Medical Center. Disclosures for the coauthors are listed in the article. Monzani reported no relevant financial relationships.

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