Why is hyperthyroidism associated with atrial fibrillation?
Many of us have evaluated for hyperthyroidism in patients with new-onset atrial fibrillation. The association between hyperthyroidism and sinus tachycardia may make sense, particularly given that other endocrine conditions associated with sympathetic surge (e.g., pheochromocytoma) show the same. However, the association with atrial fibrillation (AF) isn’t immediately apparent.
And there is an association. From large cohort studies, we know that the relative risk of AF in overt hyperthyroidism is about 3-6x above the baseline risk. In addition to that, if you have subclinical hyperthyroidism, your risk also increases in approximately a linear fashion. Even within the reference range, as free T4 increases you see this association. At the lower end, the hazard ratio is ~1.2 and increases to 1.5 at the higher end of the reference range.
There are two periods of time (early and late) where we might see this association between hyperthyroidism and AF. Within the acute hyperthyroid phase, there are hemodynamic effects and electrophysiologic effects leading to this connection.
Hyperthyroidism is a state in which there is sympathetic activation. Largely mediated by T3 these patients see an increased sensitivity to β1-adrenergic and M2-muscarinic receptors. This leads to increased heart rate and a resulting decreased atrial refractory period. A decreased effective atrial refractory period can, in itself, sustain AF if an ectopic focus develops. A re-entrant wave or spiral (rotor) is sustained by atrial myocytes with a decreased refractory period because they are primed to conduct a re-entrant impulse earlier than usual. The upshot is that an increased heart rate alone can create an environment where AF may thrive.
But, not every tachycardic or sympathetically stressed patient develops AF. It isn’t just about the hemodynamics. There are electrical aspects as well. Animal studies are helpful in understanding how the cells of the atria and pulmonary veins are responding to thyroid hormone. One study from 2002 by Chen et al in JACC examined atrial and pulmonary vein cardiomyocytes from a rabbit and incubated them with T3. They found that in the induced-hyperthyroid rabbit cells, both the atrial and pulmonary vein cardiomyocytes had a higher heart rate. This is consistent with the hemodynamic changes noted above. But, the pulmonary vein myocytes also had higher rates of both early and late afterdepolarization. These are spontaneous events apart from depolarization. None of the control cardiomyocytes had these events.
Subsequent studies have identified which ion channels are altered in the cardiomyocyte as a result of hyperthyroidism. Affected channels cause shortening of the action potential and refractory period and include multiple sodium channels and calcium channels. One calcium transporter may be familiar: the sarcoendoplasmic reticulum calcium (Ca2+) transport adenosine triphosphatase (ATPase) or SERCA. This channel moves calcium from the cytosol of the cell to the lumen of the sarcoplasmic reticulum and is directly upregulated by T3 and therefore contributes to the increased contractility of myocytes.
To summarize the acute phase: T3 directly affects the pulmonary vein cardiomyocytes via changes to their ion channel expression which causes increased afterdepolarizations. These impulses then are conducted through atrial cardiomyocytes which, at a higher sympathetic tone due to T3, have a higher heart rate with a decreased atrial refractory period. This makes them more susceptible to sustaining atrial fibrillation.
The late-phase association concerns the fact that longstanding AF can lead to fibrosis. This fibrosis, in turn, predisposes to more AF. There isn’t as deep an evidence-base. However, in hyperthyroid states, inflammatory markers including TNF-alpha, IFN-gamma, and IL6 are elevated, and cardiomyocytes are in a hypermetabolic state associated with oxidative stress. These factors (i.e., inflammation and oxidative stress) have been theorized to explain why fibrosis may occur in long-term uncontrolled hyperthyroidism and lead to an increased predisposition to AF.
There are a number of small studies showing that levothyroxine is also a risk factor for AF. The Health Improvement Network (THIN) is a large United Kingdom database on health outcomes. Researchers reviewed over 160,000 patients with hypothyroidism and over 800,000 TSH measurements. Between the range of undetectable TSH to the TSH over 10 cohort, the confidence interval for the hazard ratio of AF never crosses 1.
Smaller population studies have found some association between a TSH under 0.03 and dysrhythmias including AF. Supporting this hypothesis is a case report of a patient who had taken 10mg of levothyroxine and developed a syndrome consistent with thyroid storm. This included AF. They were treated with propylthiouracil, propranolol, and hydrocortisone.
One might wonder whether hypothyroidism protects against AF. Sadly not. If anything, there are a variety of fibrosis pathways that are also upregulated in hypothyroidism, which may predispose to AF, if anything. One place where these associations also emerge relates to any association between subclinical hyperthyroidism and AF. This is a controversial topic!
One other interesting idea is whether the medications known to reduce structural remodeling of the ventricles could reduce remodeling in the atria which predisposes to AF. One recent animal study of sacubitril/valsartan looked into this, but it isn’t ready for primetime.
Take Home Points
- Thyroid hormone also causes changes to ion channel expression in pulmonary vein cardiomyocytes, which cause increased early and late afterdepolarizations, which can trigger atrial fibrillation.
- Thyroid hormone also causes increased sensitivity to sympathetic signaling and higher heart rate. This decreases effective refractory period, which makes the conduction system more susceptible to sustaining atrial fibrillation once it has begun.
- Long-term, there is some evidence that both hyper- and hypo-thyroidism may cause fibrosis, which predisposes to more AFib.
- For more on this topic, have a look at this excellent review.
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Credits & Citation
◾️Episode written by Hannah Abrams
◾️Show notes written by Tony Breu and Hannah Abrams
◾️Audio edited by Clair Morgan of nodderly.com
Abrams HR, Cooper AZ, Breu AC. Irregularly Irregular. The Curious Clinicians Podcast. September 20, 2023.
Image credit: https://www.aclsmedicaltraining.com/atrial-fibrillation/
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