Thyrotoxicosis and angina

Commonly, research has connected “thyrotoxicosis” to angina or coronary vasospasm.  Hyperthyroidism is the usual cause of “thyrotoxicosis,” caused by toxic high levels of thyroid hormone, revealed by an abnormally low or undetectable TSH and/or high T4 and/or T3 level.  Reduction of T4/T3 levels and normalization of TSH led to resolution of their heart symptoms.

My question in reviewing these articles was “To what degree did these articles on thyrotoxicosis point to T3 as a factor in angina?” This is an important question to ask since T3 has a much more powerful effect on cells than T4.

Other research has pointed to the opposite type of thyroid dysfunction, hypothyroidism, as significantly associated with coronary vasospasm or variant angina, but has not studied T3 levels of its subjects, leading to similar questions about T3 levels and angina (Lee et al, 2015).  So, is it HIGH T3, or LOW T3, or both, that is associated with vasospasm/angina?

In addition, these articles remind us that not all thyrotoxicosis is the same, since various causes of hyperthyroidism vary in their T3 and T4 levels in serum.  Research (Carle, et al, 2013) has found that Total T3 levels are much higher than T4 levels in Graves’ disease hyperthyroidism, yielding the highest T3:T4 ratio. The same study found that Total T3 levels are significantly higher in Graves’ compared to other forms of hyperthyroidism such as “painless thyroiditis” (tT3 over 5.0 nmol/L for Graves’ disease, vs. 2.5 to 3.77 nmol/L for nine other forms of hypothyroidism, where the tT3 reference interval was 1.2–2.7 nmol/l).

NOTE: The following review involves ethical copying of limited content from journal articles within Canadian Copyright Law. See the Wikipedia article “Fair dealing in Canadian copyright law” or the Law itself, at http://laws-lois.justice.gc.ca/eng/acts/c-42/page-18.html

Thyrotoxicosis & angina articles

Zheng, W., Zhang, Y.-J., Li, S.-Y., & Liu, L.-L. (2015). Painless thyroiditis-induced acute myocardial infarction with normal coronary arteries. The American Journal of Emergency Medicine, 33(7), 983.e5.

Case report

“A 21-year-old man, without a history of tobacco use, recreational drug abuse, or inherited cardiovascular risk factors, presented with a sudden onset of chest pain when he slept. Three days prior, he had experienced a similar chest pain after drinking alcohol, which spontaneously relieved after a few minutes.

On presentation,

  • his heart rate was 95 beats per minute, and blood pressure was 168/82 mm Hg.
  • Marked ST-segment elevation in II, III, aVF, and V7 to V9 was found on electrocardiogram (ECG) (Fig. 1).
  • Levels of troponin I rose to 11.1 ng/mL and creatine phosphokinase (CK)-MB to 27.70 ng/mL (Fig. 2).
  • However, echocardiography showed no wall-motion abnormalities or ventricle dysfunction (ejection fraction, 54%).
  • Emergency coronary angiography revealed normal coronary arteries with no sign of coronary dissection or atherosclerosis (Fig. 3; Videos 1 and 2).
  • No further procedures were implemented, and medical treatment was chosen.
  • The patient had no clinical or biological signs suggestive of myocarditis, myocardial bridging, early repolarization syndrome, Behcet disease, lupus erythematosus, antiphospholipid syndrome, or Takayasu disease.

Upon 2 days’ complaining of persistent palpitation (~95-110 beats per minute) and tremor, the patient was subjected to thyroid function testing.

  • The test revealed thyrotoxicosis,
  • but the titers for antithyrotropin receptor and thyroid-stimulating antibody were negative.
  • Thyroid ultrasound showed a smooth thyroid without focal lesions.
  • A technetium Tc 99m pertechnetate scan indicated markedly low thyroid uptake, compatible with thyroiditis.

We diagnosed the patient with painless thyroiditis (thyrotoxic phase) and concluded that thyrotoxicosis had induced coronary vasospasm, resulting in AMI.

The patient was treated with diltiazem and propranolol. He did not report any chest pain during the 24-month follow-up period.

“Thyrotoxicosis alters the cardiovascular hemodynamics by increasing the heart rate, cardiac contractility, and cardiac output and by decreasing systemic vascular resistance [4,5]. In this way, thyrotoxicosis increases the risk of angina pectoris and AMI by coronary vasospasm.”

“Angina is a common symptom in patients with hyperthyroidism; however, AMI, as occurred in our patient, is infrequently observed.”

“In conclusion, thyrotoxicosis, especially induced by painless thyroiditis, should be considered when patients manifest with typical AMI but with normal angiographic results and no cardiovascular disease risk factors.”

Review commentary by Healthy Researcher Blog: The article was not specific enough on the test results that showed “thyrotoxicosis.” It did not distinguish hyperthyroidism as an excess of T4 or T3. This is surprising for an article published as recently as 2015.

However, they did usefully point out that dysfunction in thyroid hormones (the thyroid gland itself was normal) can have a significant effect on the heart that is independent of angiographic signs and cardiovascular risk factors.


Nakano, T., Konishi, T., & Takezawa, H. (1987). Vasospastic angina in thyrotoxicosis—case reports. Angiology, 38(9), 717. 

Abstract: “We encountered 2 patients with thyrotoxicosis accompanied at its onset by progressive angina. The ST segment was elevated in one patient and depressed in the other patient during the spontaneous attacks. Coronary arteriographic findings were normal during control, and spasm was induced by ergonovine. No patients had chest pain even without antianginal medication after successful treatment of thyrotoxicosis. The coronary artery may become sensitive to spasm during thyroid hormone excess even in cases without significant coronary artery disease and previous chest pain.

Case  1: 57-year-old male.

  • Pre-treatment serum levels showed excess thyroid hormones:
  • Total T3 309 ng/dl
  • Total T4 15.1 ug/dl
    • [AMA conversion 2581 nmol/L; AMA ref range 206-309 nmol/L]
  • “After normalization of thyroid function, spontaneous episodes of chest pain subsided without antianginal medication and were not induced even during treadmill exercise” (p. 719).

Case 2: 44-year-old female.

  • Pre-treatment serum levels showed excess thyroid hormones:
    • Total T3 360 ng/dl
    • Total T4 15.6 ug/dl
      • [AMA conversion 2666 nmol/L; AMA ref range 206-309 nmol/L]
  • As in Case 1, “The chest pain disappeared with normalization of thyroid function and was not observed during treadmill exercise” and “The patient was free from chest pain on only methimazole after normalization of the thyroid function” (p. 720).

Discussion

“Angina pectoris in patients with thyrotoxicosis is characterized by

  • rest and exertional angina
  • recent onset and rapid progression of angina, and
  • abrupt cessation of angina after successful treatment of thyrotoxicosis” (p. 721)

“Angina pectoris complicating thyrotoxicosis is not uncommon in the literature, and the incidence is reported by Burstein et al to be 0.5-20% (usually 10-12%)” (p. 721, italics added)

“Coronary arterial spasm seems to be the most possible cause of documented myocardial ischemia during thyroid hormone excess.” (p. 721)

“In an experimental study of the rat sympathetic system during thyroid hormone excess, an increase in β-receptors but a decrease in α-receptors, which cause vasoconstriction, were reported [Williams & Lefkowitz, 1979].” (p. 721, italics added)

“Several reports of myocardial infarction occurring in thyrotoxicosis patients with normal coronary arteries [Kotler et al, 1973; Hoshino et al, 1978; Gordon & Lenkei, 1964; Burstein et al, 1960] also deny the coincidental occurrence of the two conditions.” (p. 720, italics added)

“Furthermore, according to Featherstone’s [1983] report, hypothyroidism was induced by 131-I irradiation therapy, and chest pain recurred after the administration of levothyroxine sodium.” (p. 721 bold and italics added)

Thyroid hormones may also have a direct action on the vascular smooth muscles to enhance their sensitivity to spasm, but this action also has yet to be clarified and needs further experimental study.” (p. 721, italics added)

“During thyrotoxicosis, we must pay special attention to the possibility of coronary artery spasm in cases with chest pain and to the use of β-blockers, which may induce coronary spasm.” (p. 721, italics added)

Review commentary by Healthy Researcher Blog: it was interesting to see a 44-year-old FEMALE included in the case report.

Note that beta blockers, which block the activity of norepinephrine and epinephrine, not thyroid hormones, could induce coronary spasm in thyrotoxicosis. 


Jaber, J. A., Haque, S., Noor, H., & Ibrahim, B. (2010). Thyrotoxicosis and coronary artery spasm: case report and review of the literature. Angiology, 61(8), 807.

Abstract: A 51-year old Middle-Eastern man presented with recurrent chest pain associated with ST-segment elevation. The patient was treated with placement of a stent in the right coronary artery. He was subsequently diagnosed with severe hyperthyroidism secondary to Graves disease, which is thought to be the cause of the coronary spasm. The patient was treated with neomercazole and potassium iodide solution, and diltiazem, and nitrates with resolution of his symptoms.

This unusual case highlights the importance of considering hyperthyroidism in the differential diagnosis of recurrent chest pain and coronary artery spasm. We suggest routine thyroid function testing in patients with coronary spasm.

Case details

“He was admitted to hospital “with intermittent nonexertional chest pain.”

  • His cardiovascular history was unremarkable.
  • On examination his blood pressure was 113/57 mm Hg with a heart rate of 90 beats/min.
  • No pathological findings were detected on physical examination.
  • Serial resting electrocardiograms (ECGs) were normal.
  • Laboratory results including creatine kinase-MB fraction (CK-MB) and Troponin T were not elevated.
  • During exercise treadmill testing, the patient was able to exercise for 8 minutes, without symptoms or ECG changes.

“On September 10, 2009, he presented to Mohammed Bin Khalifa Cardiac Centre, Manama, Bahrain, with recurrent chest pain

  • coronary angiography was performed, which did not reveal any significant findings and he was discharged on the same day.

“The next day on September 11, the patient presented with recurrence of his chest pain

  • with intermittent ST-segment elevation in lead III and augmented unipolar limb lead (left leg) (AVF) along with ST depression in lead augmented unipolar limb lead (left arm) (AVL)
  • after sublingual nitroglycerin, his ECG changes reverted to baseline.
  • He underwent repeat angiography, which demonstrated intermediate stenosis in his distal right coronary artery and was assessed using intravascular ultrasound (IVUS).

“Despite optimal medical therapy and coronary stenting, the patient continued to complain of recurrent chest pain and subsequently he was admitted to Hamad General Hospital, Doha, Qatar, on October 5, 2009, with a diagnosis of unstable angina.” (p. 808)

  • Repeat coronary angiography revealed patent stent, but there was diffuse spasm in the RCA (except for the stented area), which resolved with intracoronary nitroglycerin administration.

“Later on, repeat physical examination revealed

  • the presence of fine tremor of the extremities, warm dry skin, and lid lag.
  • The thyroid gland was diffusely enlarged with a local bruit.
  • Laboratory results showed the following:
    • Thyroid-stimulating hormone (TSH) was undetectable <0.01
      mIU/L (normal range: 0.45-4.5),
    • Free T3 (FT3) was >46.1 pmol/L (normal range: 3.4-6),
    • Free thyroxine (FT4) = 40.6 pmol/L (normal range: 9-20),
    • Thyroglobulin (TG) antibody screen = 11 IU/mL (normal <4.0)
    • Thyroid-stimulating immunoglobulin (TSI) was elevated.

“The patient was treated with diltiazem and nitrates for the coronary spasm and neomercazole and potassium iodide solution for the hyperthyroidism. Five weeks laboratory evaluations were

  • TSH =0.01 mIU/L,
  • FT4 = 21 pmol/L,
  • [F]T3 = 7.7 pmol/L.

“Currently (3 months later), the patient is doing well without any further episodes of chest pain.” (p. 809)

Discussion

“This report illustrates a case of coronary spasm secondary to Graves disease and highlights the need to consider thyrotoxicosis in the differential diagnosis of angina in general and specifically for coronary spasm.” (p. 809)

“In a retrospective analysis of 325 patients diagnosed with coronary spasm in Korea between 1994 and 2000, Choie et al [ ]  reported 8 patients (4.69%) who were found to have hyperthyroidism (all had Graves disease). All had complete resolution of symptoms with therapy and continued to be asymptomatic after up to 7 years of follow-up.” (p. 809)

“In our case and in many other reported cases however, hyperthyroidism was associated with spasm in the coronary circulation as compared with vasodilatation in the peripheral vascular system. This suggests that in some patients with hyperthyroidism, the vasculature may have enhanced sensitivity to stimuli such as catecholamines. Why this condition occurs in minority of hyperthyroid patients is unknown.” (p. 809)

“Hyperthyroidism should be suspected in patients with chest pain that is thought to be secondary to vasospasm. This may occur in the absence of obvious manifestations of hyperthyroidism.” (p. 809)

Review commentary by Healthy Researcher Blog: This case shows that both T4 and T3 were extremely high, in the absence of other causal factors of chest pain or vasospasm. 

His case manifested “spasm in the coronary circulation” but the opposite effect beyond the heart, “vasodilatation in the peripheral vascular system.” This may suggest that T3 has different, possibly contradictory effects on vasodilation or vasoconstriction in coronary vs. peripheral arteries.  Could it be possible that LOW T3 would cause the opposite (constriction in peripheral arteries, dilation in coronary arteries)?

Even after treatment of his hyperthyroidism, his T3 levels were still above range, but he had no further chest pain to date at the time of writing. This makes one wonder how high above lab reference range is the cardiac danger zone for high T3?


Romero-Rodríguez, N., Cabeza Letrán, M. L., Gil Ortega, M. V., & Pradas, S. B. (2008). Thyrotoxicosis-Induced Vasospastic Angina. Revista Española de Cardiología (English Edition), 61(12), 1355–1356. http://doi.org/10.1016/S1885-5857(09)60066-9

Notes & Quotes

“To the Editor: We present 2 cases of severe vasospastic angina resistant to intensive medical treatment. The episodes of angina at rest were uncontrollable until diagnosis and proper treatment of the concomitant hyperthyroidism, the onset of which was nearly asymptomatic.”

Case 1: 75-year-old male

  • History of heart disease and heart surgery
  • Free T4 4.82 ng/dL (normal range 0.89-1.8 ng/dL)
  • TSH (thyrotropin) undetectable
  • Patient had a thyroidectomy. Angina episodes ceased.

Case 2: 50-year-old male

  • Came to hospital having acute myocardial infarction
  • Free T4 was 6.41 ng/dL (normal range 0.89-1.8 ng/dL)
  • TSH (thyrotropin) undetectable
  • “he exhibited positivity for antithyroid antibodies” and was diagnosed with Graves disease.
  • Treated with carbimazole.  No more symptoms in 8 months of follow up.

Their Discussion

“The cardiovascular effects of hyperthyroidism are well known, and are associated with a hyperandrenegeric state and an agonist effect of calcium in the myocardium [Emdin, et al, 2000]” (p. 1356).

“up to 20% of the patients with hyperthyroidism develop angina” [Masani, et al, 1995] (p. 1356).

“The present manuscript strengthens the hypothesis concerning causality in the association between hyperthyroidism and vasospastic angina” (p. 1356).

“We highlight the importance of determining thyroid hormone concentrations in cases of vasospastic angina, especially when drug resistance is observed, and even if the signs of hyperthyroidism are mild.” (p. 1356, italics added).

Review commentary by Healthy Researcher Blog: This article did not measure T3 levels. It only focused on T4 and TSH as measures of hyperthyroidism. Nevertheless, it usefully confirmed the theory of excess thyroid hormones causing vasospastic angina.


Masani, N. D., Northridge, D. B., & Hall, R. J. (1995). Severe coronary vasospasm associated with hyperthyroidism causing myocardial infarction. British Heart Journal, 74(6), 700–701.

Abstract: A 48 year old woman presented with angina after an anterior myocardial infarction and was found to be hyperthyroid. Coronary angiography showed a stenosis of the left coronary os and a long, severe stenosis of the left anterior descending artery which was partially relieved by glyceryl trinitrate. Three months later, after radioactive iodine treatment had rendered her euthyroid, repeat coronary angiography showed entirely normal coronary arteries. This unusual case establishes an association between hyperthyroidism and coronary vasospasm resulting in myocardial infarction.

Before treatment:

  • Free T4 > 100 pmol/L (normal 12-28)
  • TSH Undetectable
  • 90% blockage in coronary artery

After treatment of heart and resolution of thyroid dysfunction:

  • “There was a complete resolution of all coronary abnormalities” (700)

Discussion

Angina occurs in up to 20% of patients with thyrotoxicosis, usually because of coronary atheroma and increased sympathetic activity [Somerville & Levine, 1950].”  (p. 701, italics added)

“In common with previous observations [Somerville & Levine, 1950; Wei, et al, 1979] our case was notable for mild clinical manifestations of thyrotoxicosis despite considerable biochemical changes.”(p. 701, italics added)

“We conclude that hyperthyroidism should be considered as a cause of life-threatening myocardial ischaemia, particularly in patients without risk factors for atherosclerotic disease.” (p. 701, italics added)

Review commentary by Healthy Researcher Blog: Like the previous article, this confirmed the association between hyperthyroidism and angina/MI. 
Is it possible that these studies are more interesting to researchers because they are more dramatic and surprising than a patient who has hypothyroidism and heart disease?

The entire set of articles on thyrotoxicosis and angina admittedly applies only to severely HYPER-thyroid patients.

However, I wonder if excess Reverse T3 could be a major factor.  Increased T4 could lead to excess hormone conversion to Reverse T3 as well as T3. 

It was not studied whether these patients had more Reverse T3 than T3 in their serum.  The net effect on cells could be IMPAIRED ACCESS TO T3 despite their high serum T3 level.

References

Burstein, J., Lamberg, B. A., & Erama, E. (1960). Myocardial infarction in thyrotoxicosis. Acta Med Scand 166, 379-393.

Carle, A., Knudsen, N., Bulow Pedersen, I., Perrild, H., Ovesen, L., Banke Rasmussen, L., & Laurberg, P. (2013). Determinants of serum T4 and T3 at the time of diagnosis in nosological types of thyrotoxicosis: a population-based study. European Journal of Endocrinology 169, 537–545

Emdin, M., Pratali, L., & Iervasi, G. (2000). Abolished vagal tone associated with thyrotoxicosis triggers prinzmetal variant angina and paroxysmal atrial fibrillation. Annals of Internal Medicine, 132(8), 679.

Featherstone, H. J., & Stewart, D. K. (1983). Angina in thyrotoxicosis: Thyroid related coronary artery spasm. Arch Intern Med 143, 554-555.

Gordon, J. A., & Lenkei, S. C. (1964). Thyrotoxicosis associated with myocardial infarction. Can Med Assoc J 90, 1128-1129.

Jaber, J. A., Haque, S., Noor, H., & Ibrahim, B. (2010). Thyrotoxicosis and coronary artery spasm: case report and review of the literature. Angiology, 61(8), 807.

Lee, S., Cho, K., Kim, H., Heo, J., & Cha, T. (2015). The Impact of Subclinical Hypothyroidism or Thyroid Autoimmunity on Coronary Vasospasm in Patients
without Associated Cardiovascular Risk Factors. Korean Circulation Journal 45(2), 125-130.

Masani, N. D., Northridge, D. B., & Hall, R. J. (1995). Severe coronary vasospasm associated with hyperthyroidism causing myocardial infarction. British Heart Journal, 74(6), 700–701.

Nakano, T., Konishi, T., & Takezawa, H. (1987). Vasospastic angina in thyrotoxicosis—case reports. Angiology, 38(9), 717.

Somerville, W. & Levine, S. A. (1950). Angina pectoris and thyrotoxicosis. Br Heart J 12, 245-247.

Wei, J. Y., Genecin, A., Greene, H. L., & Achuff, S. C. (1979). Coronary spasm with ventricular fibrillation during thyrotoxicosis: Response to attaining euthyroid state. The American Journal of Cardiology, 43(2), 335–339. http://doi.org/10.1016/S0002-9149(79)80023-5


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