Key Teaching Points
•
Though the most common cardiovascular effects of hyperthyroidism are sinus tachycardia,
atrial fibrillation, and atrial or ventricular premature complexes, complete atrioventricular
(AV) block can occur, but it remains a rare occurrence.
•
Identifying underlying thyroid dysfunction in patients presenting with AV block is
critical, as treating the underlying thyroid dysfunction can help remove the stimulus
triggering the arrhythmias. In addition, medications used to treat hyperthyroidism
include beta blockers, which can be detrimental in patients with AV block.
•
There is no consensus on the management of patients with thyrotoxicosis and AV block,
and further studies need to be performed to understand the natural progression and
optimal timing and duration of device-based therapy.
Introduction
Complete heart block or third-degree atrioventricular (AV) block is a disease of the
cardiac conduction system that results in lack of electrical conduction from atria
to the ventricles. It is more common in the older patient and it is most often owing
to age-related degeneration and fibrosis of the conduction system.
1
Hypothyroidism is a known, but rather uncommon, cause of AV block, particularly in
young and middle-aged adults.
1
Hyperthyroidism is an extremely rare cause and has been described in only a few case
reports, most commonly in association with acute inflammatory states, infections,
or medications such as digoxin.2, 3, 4 We present a case of a young male patient with
symptomatic complete heart block and asystole in the setting of newly diagnosed Graves'
disease.
Case report
A 41-year-old man with no significant past medical history presented with syncope.
The patient described loss of consciousness without preceding chest pain, dyspnea,
or palpitations. Prior to this episode, the patient noted a several-day history of
subjective fevers and a nonproductive cough, but denied a history of tick bites, rashes,
or arthralgia.
Upon arrival to the hospital, he was hypertensive but vital signs and physical examination
were otherwise unremarkable. Electrocardiogram showed sinus tachycardia with a complete
heart block and an accelerated junctional rhythm (Figure 1). Initial laboratory evaluation
revealed a normal complete blood count and electrolytes (potassium 4.5 mmol/L, total
calcium 9.3 mg/dL [normal range 8.9–10.1 mg/dL], phosphorus 2.6 mg/dL [normal range
2.5–4.5 mg/dL], and magnesium 1.9 mg/dL [normal range 1.7–2.3 mg/dL]). Inflammatory
markers were mildly elevated, with a C-reactive protein of 48.9 mg/L and erythrocyte
sedimentation rate of 33 mm/h. Lyme serology was negative. Of note, he had a severely
depressed thyroid-stimulating hormone (TSH) (<0.01 mIU/L) and an elevated free thyroxine
level (T4) of 4 ng/dL (reference range 0.9–1.7 ng/dL), which was confirmed on repeat
testing.
Figure 1
Electrocardiogram acquired from the patient on presentation, which shows complete
dissociation of atrial and ventricular activity consistent with third-degree atrioventricular
block.
Echocardiography revealed a structurally normal heart with left ventricular ejection
fraction of 59%. Computed tomography angiography of the chest was negative for pulmonary
embolism and dissection. Cardiac magnetic resonance imaging (MRI) demonstrated no
evidence of myocarditis or infiltrative disease.
While hospitalized, he sustained recurrent syncope in the context of 10- and 13-second
periods of complete heart block without an escape rhythm.
Further evaluation revealed a positive thyroid receptor antibody with a level of 2.41
IU/L (normal <1.75 IU/L), highly suggestive of Graves' disease in the setting of elevated
T4 and suppressed TSH. He was treated with methimazole. Given his long periods of
recurrent asystole with syncope, temporary pacing wires were placed on initial presentation.
The patient required minimal V pacing, with rhythms mostly consistent with sinus tachycardia
and an accelerated junctional rhythm. However, given his initial presentation with
syncope and prolonged pauses, a permanent dual-chamber pacemaker was ultimately placed.
At 5 months' follow-up, thyroid hormone levels normalized and he was clinically euthyroid
on methimazole (Figure 2). He had no recurrent syncope or pre-syncope. Holter monitoring
and device interrogations showed normal sinus rhythm with atrial pacing and 1 brief
period of AV sequential pacing.
Figure 2
Change in thyroid hormone levels with therapy. A: Change in free T4 (in ng/dL), and
B: change in total T3 (in ng/dL), following initiation of methimazole (day 4 of hospitalization).
Both indices were elevated on presentation and normalized with methimazole therapy.
Discussion
Thyroid hormones, mainly mediated through the actions of tri-iodothyronine (T3), have
adrenergic, chronotropic, and inotropic effects on the heart.
5
Indeed, many of the known clinical effects of hyperthyroidism, such as tachycardia,
sweating, and palpitations, mimic a state of catecholamine excess. However, measured
plasma levels of catecholamines tend to be normal to low in hyperthyroidism,
6
suggesting that a state of heightened adrenergic sensitivity exists.
7
However, evidence for this has been conflicting, and β-adrenergic receptor knockout
mouse studies have shown similar cardiovascular effects from exposure to thyroid hormone
compared to those with intact receptors.
8
T3 results in transcriptional modulation of several components central to enhancing
contractile function, including alpha-myosin heavy chains, sarcoplasmic reticulum
proteins, calcium-activated ATPase (Ca2+-ATPase), phospholamban (a protein that regulates
calcium ion uptake into the sarcoplasmic reticulum), the Na+-K+-ATPase pump, and voltage-gated
potassium channels. Furthermore, thyroid hormones, themselves, decrease systemic vascular
resistance.
9
These effects combined result in an overall increased heart rate and cardiac output
and widened pulse pressure (Figure 3).
5
Figure 3
Schematic outlining the cardiovascular effects of thyroid hormone (mainly mediated
through T3). Thyroid hormone results in an increase in the transcription of molecules
central to contractile function, such as α-myosin heavy chain and sarcoplasmic reticulum
Ca2+-ATPase, which results in a positive inotropic effect. It also results in an increase
in adrenergic response through increased transcription of β1-adrenergic receptors
and guanine-nucleotide regulatory proteins, resulting in a positive chronotropic effect.
The hormones also have peripheral vascular effects resulting in decreased systemic
vascular resistance, which results in increased blood volume as a response through
increased renal sodium reabsorption. All these effects combined result in an increase
in cardiac output.
5
It is not surprising, therefore, that the most common cardiovascular effects of hyperthyroidism
are sinus tachycardia and atrial fibrillation.
5
Though the mechanisms of tachyarrhythmias in hyperthyroidism are therefore quite clear
(increasing the rate of systolic depolarization and diastolic repolarization, decreasing
the action potential duration and the refractory period of the atrial myocardium and
AV node
10
), the mechanism of hyperthyroidism-related bradyarrhythmias and AV block is less
well understood. Furthermore, previous cases of thyrotoxicosis causing complete heart
block that were reported in the literature were associated with other coexisting factors,
such as acute infection
3
or coadministration of cardiac medications.
2
Nevertheless, our case highlights that this presentation, which is different from
the classic atrial fibrillation arrhythmia associated with hyperthyroidism, in the
absence of other acute precipitating factors supports the postulation that thyroid
hormone can act directly on the AV node. Although the patient's cardiac MRI did not
demonstrate any obvious signs of inflammation at any point within the myocardium,
one case report describing a similar presentation—which is the only published case
report to include an autopsy, to our knowledge—demonstrated interstitial inflammation
of the AV node, the His bundle, and its branches.
11
Throughout the course of his hospitalization, various rhythms were noted, which included
sinus tachycardia, an accelerated junctional rhythm, and complete heart block. The
presence of these rhythms in the setting of thyrotoxicosis and in the absence of structural
heart disease is peculiar. An accelerated junctional rhythm arises when the rate of
an AV junctional pacemaker exceeds that of the sinus node. Although no studies have
been done to specifically evaluate the underlying pathophysiology of this arrhythmia
in states of thyrotoxicosis, it is well known that the AV node is under autonomic
regulation. Furthermore, calcium dynamics have been shown to play a key role in AV
node automaticity.
12
As previously mentioned, T3 plays a key role in regulation of molecules involved in
calcium flux, including sarcoplasmic reticulum proteins and calcium ATPase. Additional
mechanistic studies are required to further elucidate the intricacies of this arrhythmia
in this clinical setting.
However, an important clinical entity to consider is thyrotoxic periodic paralysis,
which is a condition that can occur in patients with hyperthyroidism, characterized
by abrupt onset of paralysis and hypokalemia, and can result in AV block, ventricular
fibrillation, and asystole. This condition can occur in any patient but is most commonly
seen in men of Asian descent. Common precipitants of this condition include exercise
and a carbohydrate-rich meal. Although the condition classically results in hypokalemia,
normokalemic patients have been described.
13
Though the data regarding the degree of reversibility in patients with AV block who
have their hyperthyroidism treated are lacking, perhaps owing to the rarity of this
presentation, it has been shown that in patients with thyrotoxicosis and atrial fibrillation
with no underlying valvular heart disease, 62% of patients spontaneously reverted
to sinus rhythm within 1 year after commencing treatment of their thyrotoxicosis,
and typically within 8–10 weeks after achieving a euthyroid state.
14
The other important point to consider is that medications that are often used to treat
hyperthyroidism include beta blockers, which can be detrimental in patients with AV
block.
There are scant data and no guidelines to guide the management of patients with thyrotoxicosis
who present with high-grade AV block. Our patient presented with third-degree AV block
along with symptomatic periods of asystole. Current guidelines recommend permanent
pacing for patients with third-degree heart block.
15
The guidelines also, however, stress that potentially reversible causes such as medications,
ischemia/infarction, electrolyte abnormalities, and Lyme disease should ideally not
be treated with permanent pacing.
15
There is no specific mention of advanced AV block in the specific setting of thyroid
dysfunction.
15
There is no clear indication as to how long pacing is required or at what point explanting
the pacemaker could be safely considered. One study, by Ozcan and colleagues,
4
followed 21 patients with AV block associated with hyperthyroidism, of whom 20 patients
(95.2%) underwent pacemaker implantation. Nine patients had normalization of their
TSH with therapy, but 8 of those patients had persistent or recurrent AV block. Meanwhile,
12 patients had persistently low TSH levels despite therapy and all of those patients
had persistent AV block during the initial hospital follow-up period (21 days), and
10 of the 12 patients had persistent AV block and were therefore pacemaker dependent
on extended follow-up. It is important to note that the time to resolution of the
AV block after starting medical therapy was more than 21 days, and therefore, prolonged
temporary pacing is often not a reasonable option, which makes implantation of a permanent
pacemaker a plausible option despite this being a “transient risk factor.” Although
this study was limited by a small sample size and a short duration of follow-up, it
highlights that AV dysfunction does persist in a substantial proportion of patients
despite treatment of their underlying thyroid dysfunction, in contrast to the high
degree of reversibility of atrial fibrillation once the underlying hyperthyroidism
is treated.
Conclusion
We present a case of symptomatic complete heart block and asystole in the setting
of newly diagnosed Graves' disease. Although hyperthyroidism is a known but rare cause
of advanced AV block, there are insufficient data on optimal management of these patients,
especially regarding device implantation. Further studies are required to better understand
the degree of reversibility of AV block in this setting and the optimal timing and
duration of cardiac pacing.