Refractory Vasomotor Angina in the Setting of Subclinical Hyperthyroidism: A Case Report Demonstrating Both Focal and Segmental

Vasomotor angina is a diagnostically and therapeutically challenging cause of myocardial ischemia. In many cases, affected patients undergo multiple hospitalizations and complex invasive testing, without a definitive diagnosis for years. Even after diagnosis of variant and vasospastic angina, there may be an occult underlying condition that contributes to vasospasm activity and presents an impediment to successful therapy. We report such a case of refractory rest angina with electrocardiographic (ECG) changes that eluded diagnosis and effective therapy of the inciting cause, subclinical hyperthyroidism, for over 4 years. Case Report. A 69-year-old Caucasian female presented with a 4-year history of frequent nocturnal and rest angina refractory to conventional antianginal therapy. She had been empirically treated with diltiazem SR 300 mg, nitroglycerin (NTG) patch, sublingual NTG tablets and aspirin. A diagnostic cardiac catheterization was done soon after her initial presentation and was repeated 4 years later when she reported a particularly severe episode of angina at rest accompanied by dyspnea and diaphoresis lasting 45 minutes. Unfortunately, she did not seek medical attention until 2 weeks after the episode, precluding the use of cardiac enzymes routinely available at the time. An ECG showed deep and symmetric T-wave inversions in leads V3–V6, a change from previously normal tests (Figure 1). Both cardiac catheterizations excluded significant coronary artery disease and left ventricular angiography revealed normal wall motion and function. Despite frequent rest angina, the patient remained fully active with only rare anginal episodes during exertion. She denied any history of hypertension, diabetes mellitus, tobacco use, hypercholesterolemia or family history of coronary artery disease. She denied any other significant ongoing medical problems. Physical exam revealed a thin but healthy appearing white female (body mass index = 21 kg/m2). Blood pressure was 150/80 mmHg. Heart rate was regular and 72 beats/minute. Cardiovascular exam was normal. Laboratory values were all normal, including a total cholesterol of 139 mg/dl. She continued to have frequent rest angina and was referred to a tertiary center for provocative testing for coronary artery spasm. After holding all medications for over 24 hours, a baseline left coronary arteriogram was performed (Figure 2A). Just after this, the patient had spontaneous chest pressure and ST-segment elevation in the monitored lead V5. A test injection showed severe focal constriction (> 90% luminal diameter narrowing by visual estimation) of the proximal left anterior descending (LAD) coronary artery. Symptoms and ECG changes resolved rapidly (within 2 minutes) without pharmacologic therapy and repeat test injection demonstrated resolution of constriction. Because of the brevity of the episode, it was not documented by cineangiography. After an additional 3 minutes, formal testing for spasm was performed. Graded infusions of acetylcholine (ACh) (10-8, 10-7, 10-6 and 2 x 10-6 Molar) were administered into the left main artery, each over 2 minutes, using an infusion catheter and syringe pump. Left coronary arteriography was performed and coronary dimensions were measured following each infusion. Epicardial diameter increased in the proximal circumflex artery by > 20% in response to the 2 highest infusion rates of ACh, but decreased in the proximal LAD by >20%. There was diffuse segmental constriction (> 80% luminal diameter narrowing by visual estimation) of the mid LAD in response to the peak graded infusion of ACh (Figure 2B). After 300 µg of intracoronary NTG, both vessels dilated by > 50% compared to baseline (Figure 2C) and appeared angiographically normal. The patient was placed on enalapril 10 mg twice a day in addition to her other medications. She continued to have frequent episodes of both nocturnal and rest angina. In a 1-month period following the procedure, she kept a log that documented 27 episodes of rest angina requiring 1–2 sublingual NTG tablets each. She additionally complained of episodes of dyspnea at rest and palpitations. A stress thallium test was performed to rule out exercise-induced spasm and arrhythmias. This test was negative for symptoms, ECG and rhythm changes, and perfusion defects. An echocardiogram revealed normal chambers, normal valves and normal indexed left ventricular mass. Blood was sent for thyroid panel measurements to include high sensitivity assay of thyroid stimulating hormone (TSH). TSH was nearly undetectable on both initial and repeat testing, although tri-iodothyronine (T3) and free thyroxine (T4) were not grossly elevated, consistent with the diagnosis of subclinical hyperthyroidism [TSH = 0.03 µU/ml (normal = 0.35–4.94 µU/ml); T3 = 183 ng/dl (normal = 60–181 ng/dl); free T4 = 1.07 ng/dl (normal = 0.7–1.48 ng/dl)]. After endocrine consultation, the diagnosis of Grave’s Disease was made and the patient was treated initially with methimazole (Tapazole), then with I-131. Within 1 month of starting treatment with methimazole, she had significant improvement in anginal symptoms. After thyroid ablation, levothyroxine replacement therapy was begun and adjusted. One year later, she was fully active with rare episodes of mild angina. At that time, the patient was demonstrated to have mild subclinical hypothyroidism (TSH = 7.5 µU/ml; T3 = 107 ng/dl; free T4 = 0.89 ng/dl). During follow-up 2 years later, the patient complained of a recent increase in rest angina. Review of thyroid function tests by her cardiologist revealed suppression of TSH on the prescribed replacement dose (TSH = 0.15 µU/ml; free T4 = 1.91 ng/dl). After consultation with her endocrinologist, the dosage was reduced with subsequent normalization of TSH and remission of angina. Discussion. We describe a case of vasomotor angina secondary to coronary artery vasoconstriction, both focal and segmental, which remained refractory to medical therapy until diagnosis and treatment of Grave’s Disease, presenting asymptomatically as subclinical hyperthyroidism. Though coronary artery spasm has been described previously with known hyperthyroid disease,^1,2 ours is the first reported case occurring in the setting of subclinical hyperthyroidism, diagnosed 4.5 years after the patient’s initial presentation. Our case is also unique because of subsequent inadvertent rechallenge with excessive levothyroxine resulting in recurrent suppression of TSH and increase in rest angina that resolved only after downward adjustment of thyroid hormone and attainment of the euthyroid state. Finally, this is the first case of preclinical hyperthyroidism in which provocative invasive testing for spasm was performed using the agent acetylcholine, an autonomic neurotransmitter of particular interest because it has been implicated in the mechanism of spasm and is additionally altered in hyperthyroid disease. The precise mechanism of coronary artery spasm and vasoconstriction in hyperthyroid disease states remains controversial, but certain pertinent facts are clear. First, thyroid hormone causes vasodilation through a direct effect of tri-iodothyronine on vascular smooth muscle cells, which promotes relaxation.³ Thus, thyroid hormone itself is unlikely to be the cause of coronary artery spasm. Furthermore, though hyperthyroidism resembles a state of hyperadrenergic activity, serum concentrations of catecholamines are not increased, nor is there enhanced sensitivity to adrenergic stimulation. Second, hyperthyroidism is associated with changes in autonomic function, resulting in an increase in sympathetic and a decrease in parasympathetic tone.³ The net effect of hyperthyroid disease on coronary vessels is not clear, but includes the contributions of increased norepinephrine release locally because of increased sympathetic tone and reduced acetylcholine release due to decreased parasympathetic tone. The autonomic nervous system has also been implicated in the etiology of variant angina. Parasympathetic tone is increased during the nocturnal period, a time classically associated with increased activity of variant angina. Heart rate variability studies have shown conflicting results, suggesting increased parasympathetic activity on one hand and withdrawal of activity on the other, in different ethnic patient groups.⁴ For causation of focal coronary artery spasm, some have speculated that the segment involved must also have intrinsic hyperreactive qualities.⁵ This line of reasoning is supported by the fact that focal coronary artery spasm can be caused by multiple pharmacologic agonists in the same subject, including ergonovine, serotonin and ACh. The etiology of this post-receptoral smooth muscle hyperreactivity is an important area of future research. An interesting feature of this case is the result of provocative testing for coronary artery spasm. Spontaneous coronary artery spasm occurred in the proximal LAD just after the first coronary artery contrast injection after withholding chronically administered vasoactive medications. After rapid resolution of spasm without intervention, graded intracoronary infusion of acetylcholine did not cause focal provoked spasm at the same site, but rather, severe segmental mid LAD constriction. Segmental or generalized, as opposed to focal coronary vasoconstriction, has been more commonly reported among Japanese patients with the diagnosis of variant angina and is more frequently reported when ACh is the agonist used.⁴ Mechanisms thought to be consistent with segmental or generalized hyperreactivity include autonomic nervous system imbalance and endothelial dysfunction. Conclusion. We report a case of refractory rest angina related to unrecognized subclinical hyperthyroidism in which both spontaneous focal coronary artery spasm and severe segmental constriction were demonstrated in contiguous arterial segments in the LAD. Despite aggressive antianginal therapy, treatment was largely unsuccessful until diagnosis and therapy for Grave’s Disease, which presented asymptomatically. This case reminds us that vasomotor angina may not be a definitive diagnosis and, in some cases, an occult underlying condition contributes to vasospasm activity.

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