BERN, SWITZERLAND — Higher levels of free thyroxine (FT4) within the normal range are associated with a significant increased risk of new-onset atrial fibrillation, according to a new systematic review[1].
Thyroid-stimulating hormone (TSH) levels in the normal or subclinical hypothyroid range, however, were not associated with new-onset AF events.
“It’s well-known that overt hyperthyroidism and also subclinical hyperthyroidism are associated with atrial fibrillation, but what’s new is that we showed that it’s actually free thyroxine within the normal range and not TSH that dictates the risk in euthyroid persons,” first author Dr Christine Baumgartner (Bern University Hospital, Switzerland) told theheart.org | Medscape Cardiology.
Higher FT4 levels may be an additive risk factor for adverse cardiac outcomes, but FT4 is not ready for use as a screening tool in euthyroid patients, Baumgartner and her colleagues note in their October 23, 2017 online report in Circulation.
“Free thyroxine might be helpful to assess atrial-fibrillation risk in patients, but right now we can’t recommend measuring free thyroxine because we would still need to know that we can do something about it to decrease their atrial-fibrillation risk,” she said.
The investigators looked at individual data on 30,085 participants age 40 or older (median age 69) from 11 prospective cohort studies. Of these, 1958 (6.5%) had subclinical hypothyroidism at baseline and 2574 (8.6%) developed AF over 278,955 person-years of follow-up. The reference range for TSH was 0.45–4.49 mIU/L and for FT4 was based on study-specific cutoffs.
Compared with the lowest FT4 quartile in the normal range, AF risk increased 17% in the second quartile (hazard ratio 1.17, 95% CI 1.02–1.35), 25% in the third quartile (HR 1.25, 95% CI 1.09–1.43), and 45% in the highest quartile (HR 1.45, 95% CI 1.26–1.66) after adjustment for age and sex.
Sensitivity analyses and multivariable analyses yielded similar results. There was no association between FT4 levels and AF risk in patients with previous CV disease, but this finding may be affected by selection bias since patients with prevalent AF at baseline were excluded, Baumgartner and colleagues note.
Increasing FT4 levels were associated with higher AF risk in 1146 thyroxine users, most of whom had a FT4 level in the highest quartile. Their relatively small numbers, however, precludes meaningful interpretation of the AF risk associated with FT4 levels in those on thyroxine, one of the most frequently prescribed drugs in the US.
No association was found in age- and sex-adjusted analyses between AF risk and TSH levels in the reference range or for subclinical hypothyroidism.
The results align with data from two recent population-based studies including the investigators’ recent report[2] from the Rotterdam Study showing an increased 10-year risk of AF with higher FT4 levels within the normal range, particularly in younger participants <65 years.
The second study in older adults[3] showed that higher FT4 within the normal range was positively associated with mortality, AF, and heart failure. In contrast, TSH within the normal range but not FT4 was associated with dementia, suggesting that thyroid metabolism and action differ between target organs such as the heart and brain, Baumgartner and colleagues write.
While TSH is typically the first test used to evaluate thyroid function and thought to be more sensitive than FT4 to predict outcomes, they point out that TSH is a marker of pituitary effects of thyroid function, whereas FT4 is converted to triiodothyronine, which executes its effects on end-organs.
“We think free thyroxine has a more direct function at the level of the heart than TSH, so that’s why we think we can see this association between thyroxine and atrial fibrillation and why other researchers have also seen an association with sudden cardiac death and high blood pressure,” Baumgartner said.
The study was supported by grants from the Swiss National Science Foundation and Swiss Heart Foundation. Baumgartner reports no relevant financial relationships. Disclosures for the coauthors are listed in the paper.
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