The association between hyperthyroidism and increased atrial fibrillation (AFib) risk has been well-recognized for decades. However, a new study published in JAMA Cardiology adds a new dimension to risk assessment, demonstrating that AFib/flutter risk rises on a sliding scale, even within clinically normal thyroid stimulating hormone (TSH) ranges.
In a phenome-wide association study (PheWAS), researchers analyzed 37,154 patient records, looking for associations between genetically-determined thyrotropin levels and AFib diagnoses. They found an overall correlation, which was consistent with expectations. However, when they excluded the 9,801 patients who had a diagnosed thyroid disorder, the AFib association persisted. This had never been established before, and suggests that genetically-determined variation in thyroid function, even within “normal ranges,” is a risk factor for AFib.
“The clinical implications are significant,” said Jonathan Mosley, M.D., an internal medicine specialist at Vanderbilt University Medical Center and investigator with the study. “There can be a tendency to treat the numbers and not the patient. This study suggests caution in prescribing levothyroxine for a patient who may have TSH levels on the low end of normal, but who feels well, for example. It also suggests perhaps being more aggressive in prescribing thyroid-blocking agents to some patients at the higher end of the normal range, even though they may be asymptomatic.”
eMERGE’s Big Data Uncovers Associations
The study was funded by the American Heart Association’s Strategically Focused Research Network (SFRN), a comprehensive research program promoting AFib prevention and treatment. It serves as proof-of-concept under the SFRN aim of “leveraging genetic methods in conjunction with electronic health records to discover mechanisms of disease that contribute to atrial fibrillation.”
“Membership in the Electronic Medical Records and Genomics (eMERGE) Network gives us a wealth of such data for hypothesis-generating or discovery experiments like this one,” Mosley said. While data are available on a large cohort of individuals with AFib, accessing information on patients’ thyroid function is less straightforward. TSH levels are not universally collected. Instead, researchers relied on data that is available — the genetic factors that modulate levels of thyroid hormone.
“No matter what your actual thyroid hormone levels are, if your genetics cause them to be higher than someone else’s, you have more risk. It’s a continuum.”
“While the genetic component is only one of many influences on thyroid function, the fact that it’s been controlling a person’s levels for decades makes it the most meaningful parameter we could have used,” Mosley said. “We’ve long known that individuals who have high levels of thyroid hormone and associated clinical symptoms — weight loss, racing heart, diarrhea, fatigue and sleep problems — are prone to AFib. We found that no matter what your actual thyroid hormone levels are, if your genetics cause them to be higher than someone else’s, you have more risk. It’s a continuum.”
Clinical Implications
Knowing that AFib risk rises on a continuum both outside and inside the normal range changes decision processes for the clinician. “With no downside identified, it was easy to prescribe levothyroxine for patients at the low end of the range for things like improving mood or boosting metabolism,” Mosley said. “These findings make that decision more complex. It’s a little like what we are learning about testosterone replacement therapy. Treatment is not always benign. It requires looking at the whole patient.”
The study also supports an argument for routine TSH level screening, particularly of elderly people, who are more prone to AFib. This new understanding may call into question a preemptive decision to treat moderately low thyroid. It may also prompt a clinician to prescribe a thyroid hormone blocker to a patient with AFib or at high risk for AFib, if their TSH levels are near the higher end of normal.
Extending the Search for AFib Correlates
Mosley’s team is embarking on new studies to understand how different physiological processes contribute to AFib risk. Inflammation is the next variable they are targeting. “One study we are doing looks at procedures like ablation that are known to be associated with a lot of inflammation, and which carry a high AFib recurrence rate,” he say. “We want to see if treating patients with anti-inflammatory drugs decreases their risk.”
His team will also investigate genetic risk factors that predispose people to overactivated inflammatory responses. “We want to look at people with conditions like obesity or autoimmune diseases, where we know inflammatory processes are inappropriately activated, to see if there are genetic factors that also predispose them to AFib,” Mosley said.
