Refractory Prinzmetal Angina Treated with Cyproheptadine

Case Reports

Patient 1

A 65-year-old Spanish man with a history of labile hypertension and mild hyperlipidemia had his first episode of chest pain in 1986 when he presented to a hospital in Spain with ST-segment elevations in V2 to V4 associated with an episode of ventricular tachycardia. He responded to intravenous nitroglycerin and had serial normal levels of creatine kinase. Subsequent coronary angiography showed normal coronary anatomy. He was discharged on isosorbide dinitrate (40 mg every 8 hours for 4 years). From 1986 through 1989, the patient had several episodes of atypical chest pain. In 1990, the patient had a crescendo anginal pattern and again presented with ST elevation in V2 to V6 and had no evidence of infarction. From 1990 to the present, there were nine emergency admissions for chest pain not associated with increased levels of creatine kinase, despite treatment with oral, topical, and sublingual nitrates and with two calcium antagonists, diltiazem CD (240 mg daily) and nifedipine XL (90 mg daily). The patient had four exercise tests that were negative for ischemia and had a repeat cardiac catheterization in 1992, all of which were normal.

The patient was admitted to our hospital and had a cardiac catheterization. He was challenged with 0.5 mg of ergonovine (Ergotrate Maleate; Eli Lilly & Co., Indianapolis, Indiana) that elicited a strongly positive reaction as evidenced by diffuse vasospasm and chest pain, which were associated with bradyarrhythmia. The patient started to receive cyproheptadine (4 mg every 8 hours) as well as isosorbide dinitrate (40 mg every 8 hours) and ticlopidine (250 mg twice a day). Additional tests included 24-hour collection of urine for levels of 5-hydroxyindoleacetic acid, vanillylmandelic acid, and metanephrines, as well as serum thyroid-stimulating hormone and prothrombin time, which were all within normal limits. The fasting level of total plasma cholesterol was 6.78 mmol/L, and the level of high-density lipoprotein was 1.03 mmol/L. The platelet aggregation study showed increased spontaneous aggregation but normal responses to collagen, adenosine diphosphate, and ristocetin. The patient had no further episodes of chest pain, completed a vigorous cardiac rehabilitation regimen, and returned to Spain without symptoms.

Patient 2

In 1989, a 44-year-old Hispanic woman with a history of hypercholesterolemia and a 30-year smoking history (one pack a day) presented with her first episode of severe chest pain and left arm numbness, associated with 2- to 3-mm ST elevations in V1 to V5 and inferior ST-segment depression. The patient had cardiac catheterization that showed normal coronary arteries and a normal left ventriculogram. During the procedure, the catheter caused coronary spasm of the right coronary artery that reversed with nitroglycerin. The patient had normal serial levels of creatine kinase and was treated for Prinzmetal angina with isosorbide dinitrate (40 mg every 8 hours) and two calcium antagonists, diltiazem (120 mg three times a day) and verapamil SR (240 mg daily). Her medical history indicated treatment for asthma since 1978 with theophylline (300 mg twice a day) and albuterol (two puffs four times a day) and the occurrence of migraine headaches since the age of 18 years, which were not chronically treated. Further evaluation included an echocardiogram that showed mitral valve prolapse and an ejection fraction of 62%. Her fasting plasma cholesterol level was 7.03 mmol/L, the high-density lipoprotein level was 1.04 mmol/L, and triglyceride levels were normal. The patient had an exercise tolerance test that was negative for ischemia. The patient had several subsequent episodes of crushing substernal chest pain associated with dyspnea, exacerbation of her previously quiescent asthma, diaphoresis, and electrocardiographic evidence of ischemia responsive to intravenous nitroglycerin. Six months after her initial presentation, the patient had a subendocardial myocardial infarction after a prolonged episode of refractory chest pain. A repeat cardiac catheterization was done showing a 90% stenosis of the mid-left anterior descending artery that resolved completely with nitroglycerin. Recurrent symptoms necessitating hospitalization every 3 to 4 weeks and concomitant hypotension from the medications were so disabling that the patient was considered for possible autotransplantation (that is, denervation of the heart and sympathectomy). The patient started to receive cyproheptadine for Prinzmetal angina unresponsive to the maximal calcium-channel blocker and nitrate therapy; during the next 4 months, emergency department visits decreased markedly. Presently, the patient is residing in Florida and has approximately one episode of chest pain every 6 months and has had no further myocardial infarctions.

Discussion

Serotonin is an important endocrine mediator of coronary vasospasm [3-7]. Serotonin is produced by the enterochromaffin cells in the gut and is degraded by the liver as well as lung endothelium; the excess is stored in platelet granules [1]. After aggregation, platelets release serotonin, which causes vasoconstriction or vasodilatation depending on the presence or absence of intact endothelium. Serotonin also serves as an amplifying agent in a positive feedback loop for platelet aggregation [1]. Damage to the endothelium either by denudation [3], as seen with angioplasty, by repetitive episodes of spasm leading to ischemia with disruption of endothelial integrity and possible intramural hemorrhage [8], or by dysfunction without denudation impairs serotonin-mediated endothelial release of nitric oxide and allows direct contact of serotonin with vascular smooth muscle, resulting in vasoconstriction. Increased levels of plasma cholesterol cause endothelial dysfunction without denudation, abnormal vasoconstrictor responses to acetylcholine, and abnormal levels of circulating and tissue (endothelial and myointimal cells) endothelin [9].

Although initial limited experience with the use of the oral serotonin receptor antagonist ketanserin (Janssen Research Foundation, Piscataway, New Jersey) in the treatment of variant angina has been disappointing [7], we successfully used cyproheptadine (a 5-hydroxytryptamine antagonist as well as a mild antihistamine) to treat variant angina in our two patients who were refractory to standard treatment with calcium-channel antagonists and nitrates. Substantial advances in understanding serotonin receptor “families” [10] and the unique physiologic properties of the individual antagonists suggest that different antagonists may have clinical benefit. Certain subsets of patients with abnormal baseline platelet aggregation (patient 1) or with hypothetically increased levels of serum endothelin-1 may be uniquely more responsive to antiserotonergic therapy [7].

Our data show that a subset of patients with Prinzmetal angina who are refractory to nitrates and calcium-channel antagonists respond to antiserotonergic therapy. Identification of this group of patients requires investigation. Further clinical trials need to be done in selected patients to confirm our results.