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Studies refine relationship between AF, thyroid conditions
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Modifications in thyroid activity may be an effective strategy in preventing atrial fibrillation, according to two studies published in JAMA Cardiology.
Genetic associations
Christina Ellervik, MD, PhD, MSci, DMSci, associate director of clinical chemistry in the department of laboratory medicine at Boston Children’s Hospital, and colleagues conducted a study to determine whether thyroid traits had any involvement in AF.
The researchers performed Mendelian randomization with genetic risk scores on 7,679 patients with AF and 49,233 controls without AF from 11 studies. Information on thyrotropin levels were available for patients in eight of the studies, and free thyroxine data were available for patients in seven studies.
The genetic risk score included four free thyroxine-associated single nucleotide polymorphisms. Researchers also assessed the potential relevance of a thyrotropin levels within the reference range and a set of thyroid instruments for free thyroxine, in addition to hyperthyroidism, hypothyroidism and thyroid antibodies.
Of the patients in this study, the mean age was 62 years and 29.7% were men.
Levels of free thyroxine related to incident AF had a pooled HR of 1.55 (95% CI, 1.09-2.2; I2 = 76%). In multivariable-adjusted analyses, the pooled OR for prevalent AF was 2.8 (95% CI, 1.41-5.54; I2 = 64%).
The genetic risk score was linked to an increase in free thyroxine (0.082 standard deviation; standard error = 0.007; P < .001), although this was not seen for prevalent AF (OR = 1.32; 95% CI, 0.64-2.73) or incident AF (RR = 0.84; 95% CI, 0.62-1.14).
Gene-based free thyroxine within the reference range was also not linked to AF (OR = 1.01; 95% CI, 0.89-1.14). AF was associated with a gene-based increase in the ratio of free triiodothyronine to free thyroxine (OR = 1.33; 95% CI, 1.08-1.63), hypothyroidism (OR = 0.94; 95% CI, 0.9-0.99) and increased thyrotropin (OR = 0.88; 95% CI, 0.84-0.92). These results were robust in tests of horizontal pleiotropy.
The association with AF was not seen in the subset of hypothyroidism single nucleotide polymorphisms that were involved in thyroid peroxidase antibodies and autoimmunity, although gene-based hyperthyroidism was linked to AF (OR = 1.31; 95% CI, 1.05-1.63) with evidence of horizontal pleiotropy (P = .045).
“Genetically increased [free thyroxine] within the reference range was not associated with AF, and the current lack of additional genetic instruments, particularly for [free triiodothyronine] makes it difficult to infer a specific causal agent in the link between thyroid function and AF,” Ellervik and colleagues wrote.
Predictors of thyroid function, AF
In another study published in JAMA Cardiology, Joe-Elie Salem, MD, PhD, postdoctoral research fellow of cardio-oncology at Vanderbilt University Medical Center, and colleagues found that a genetically determined variation in thyroid function within an acceptable range is a risk factor for AF.
Researchers analyzed 1,318 phenotypes linked to a polygenic predictor of thyrotropin levels in 37,154 patients (52% men). Patients who had AF had documented AF by ECG and/or two outpatient diagnoses or one inpatient diagnosis of AF.
The thyrotropin polygenic predictor was inversely associated with hyperthyroidism diagnoses (OR = 0.64; 95% CI, 0.54-0.74) and positively associated with hypothyroidism (OR = 1.1; 95% CI, 1.07-1.14). The top association among nonthyroid associations was AF/atrial flutter (OR = 0.93; 95% CI, 0.9-0.95). When excluding patients without a thyroid-related disease, the association with AF persisted (OR = 0.91; 95% CI, 0.88-0.95).
An inverse-variance weighted average meta-analysis was performed to replicate the association with 17,931 patients with AF and 115,142 controls from a genome-wide association study. Each standard deviation increase in predicted thyrotropin was linked to decreased risk for AF (OR = 0.86; 95% CI, 0.79-0.93).
In a group of patients with AF (n = 745) and controls (1,680) who were older than 55 years, levels of thyrotropin that were within the normal range were inversely associated with the risk for AF (OR = 0.91; 95% CI, 0.83-0.99).
“The clinical decision to treat subclinical thyroid disease should incorporate the risk for AF, as antithyroid medications to treat hyperthyroidism may reduce AF risk and thyroid hormone replacement for hypothyroidism may increase AF risk,” Salem and colleagues wrote. “Interestingly, it has also been shown recently that thyrotropin may have direct electrophysiological effects in rat ventricular myocytes, although the precise mechanisms for the association are not well-defined.”
In a related editorial, Jason D. Roberts, MD, MAS, cardiac electrophysiologist at the University of Western Ontario in London, Canada, wrote: “The ubiquitous importance of thyroid function to physiological processes throughout the body complicates the potential to leverage modification of thyroid activity as an AF preventive strategy; however, the findings emphasize the relevance of considering AF when deciding to treat subclinical forms of thyroid disease. It is conceivable that improved insight into the molecular mechanisms responsible for the impact of thyroid function on AF risk may help to further unravel the complex pathogenesis of the arrhythmia and lead to novel therapeutic strategies.” – by Darlene Dobkowski
References:
Ellervik C, et al. JAMA Cardiol. 2019;doi:10.1001/jamacardio.2018.4635.
Roberts JD. JAMA Cardiol. 2019;doi:10.1001/jamacardio.2018.4614.
Salem JE, et al. JAMA Cardiol. 2019;doi:10.1001/jamacardio.2018.4615.
Disclosures: Ellervik reports no relevant financial disclosures. Roche Diagnostics provided the reagents for thyroid assays in the study performed by Ellervik and colleagues. Salem reports he received grants from Fondation Recherche Medicale. The study by Salem and colleagues was supported by Fondation Recherche Medicale and the American Heart Association. Roberts reports he is supported by the Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, the Cardiac Arrhythmia Network of Canada, the Canadian Stroke Prevention Intervention Network and the Marianne Barrie Philanthropic Fund. Please see the studies for all other authors’ relevant financial disclosures.