|Home | About | Journals | Submit | Contact Us | Français|
Billions of dollars are spent annually in the United States in the largely unregulated market of dietary supplements. Many of these supplements are marketed as weight-loss and athletic-performance-enhancement products. The association of various ephedra-containing products with adverse cardiovascular events has led to a ban on the sale of these products by the U.S. Food and Drug Administration. The result has been the emergence of new formulations marketed for weight loss and athletic-performance enhancement that are “ephedra-free” but contain other sympathomimetic substances, the safety of which has not been established.
We present the case of a previously healthy 24-year-old man who presented with an ST-segment-elevation myocardial infarction (STEMI) within hours of taking the ephedra-free product Nutrex Lipo-6x®. Emergent coronary angiography revealed the presence of extensive, diffuse thrombus in the left anterior descending coronary artery. The patient had no risk factors for coronary artery disease or myocardial infarction; this includes the absence of a hypercoagulable state and the absence of a history of illicit drug use. This case of STEMI—associated as it is with the use of a synephrine-containing product by a person without risk factors for coronary artery disease—is to our knowledge the 1st reported in the literature. We discuss the patient's evaluation and clinical course, and we review the literature with respect to synephrine-containing dietary supplements. On the basis of synephrine's chemical composition and mechanism of action, we propose a direct association between this patient's use of Nutrex Lipo-6x® and his STEMI.
Each year in the United States, over $20 billion is spent on dietary supplements, a significant proportion of which are marketed as weight-loss and athletic-performance-enhancement products. Severe neurologic and cardiovascular complications—including stroke, seizure, myocardial infarction, and sudden death1,2—have been reported in association with ephedra and ephedrine-alkaloid-containing supplements. A major study has reported more than 16,000 adverse events associated with the use of ephedra-containing dietary supplements.3 As a result, the U.S. Food and Drug Administration (FDA) determined that ephedra and ephedrine-containing supplements are unsafe for unregulated use and prohibited their sale beginning in April 2004.4
The result has been the emergence of new formulations marketed for weight loss and athletic-performance enhancement that are “ephedra-free” but contain other sympathomimetic substances, the safety of which has not been established. Many of these products contain synephrine, a sympathetic adrenergic agonist that is structurally related to ephedrine.
Although an expanding body of literature reports adverse cardiovascular outcomes in association with the use of synephrine-containing products, the case reported here is, to our knowledge, the 1st in which a person with no history of identifiable cardiovascular risk factors experienced STEMI shortly after ingesting a synephrine-containing dietary supplement. We provide a review of the literature to date, discuss the pharmacologic actions of synephrine, and implicate synephrine as the possible causative agent, on the basis of its mechanism of action, for this case of ST-segment-elevation myocardial infarction (STEMI).
A previously healthy 24-year-old black man was transferred to our cardiac care unit from a nearby hospital after presenting with acute-onset, “crushing,” mid-sternal chest pain. His symptoms had begun while he was seated at his workstation after having exercised for 2 hours on the morning of presentation; he had stopped exercising approximately 30 minutes before the onset of his symptoms. His chest pain was accompanied by shortness of breath, anxiousness, diaphoresis, and 4 episodes of emesis. He had no history of diabetes, hypertension, hyperlipidemia, or cigarette smoking, but was an infrequent cigar smoker (approximately 3 cigars per year). He had no family history of early coronary artery disease or sudden death. He denied use of cocaine, amphetamines, hormones, steroids, alcohol, or other recreational drugs.
The patient described an exercise regimen consisting of weight-training and aerobic activity 5 times a week, for 2 hours each time; 2 times per week, before exercise, he ingested 1 capsule of Nutrex Lipo-6x® (Nutrex Research, Inc.; Oviedo, Fla). Although he admitted to prior use of other weight-loss products (Hydroxycut®, Stacker 2®, and Stacker 3®), he denied the use of any of these products since beginning Nutrex Lipo-6x, approximately 3 weeks before presentation. On the morning of presentation, the patient had taken 1 Nutrex Lipo-6x capsule, along with a caffeine-containing energy drink, and then had engaged in his usual exercise routine. He denied ever having exceeded the manufacturer's recommended dose (as indicated on the product label).
Physical examination revealed a well-developed young man in moderate distress. He was afebrile. His blood pressure was 141/81 mmHg, his heart rate was 62 beats/min, and his respiratory rate was 16 breaths/min. He had no jugular venous distention, and his lungs were clear to auscultation in all fields. His chest was not tender to palpation. Cardiac auscultation revealed an S4 gallop with a normal S1 and S2. The electrocardiogram revealed sinus bradycardia with 3-to 6-mm ST-segment elevations in leads II, III, aVF, and V3 through V6 (Fig. 1). Initial laboratory studies, within 4 hours of the onset of his symptoms, were remarkable for a white blood cell count of 17,100 cells/mm3, a creatine kinase level of 409 U/L, a creatine kinase MB fraction of 2.4 ng/mL, and a troponin I level of 0.04 ng/mL. He had been given aspirin, subcutaneous enoxaparin, sublingual nitroglycerin, and intravenous morphine at presentation, which did not relieve his chest pain or ST elevation.
The patient was taken for emergent cardiac angiography within 1 hour of presentation, which revealed nonocclusive thrombus in the proximal left anterior descending coronary artery (LAD) and total thrombotic occlusion of the distal LAD (Fig. 2). Eptifibatide was started as a bolus, followed by an infusion. A Pronto® V3 thrombus extraction catheter (Vascular Solutions, Inc.; Minneapolis, Minn) was passed through the thrombus 4 times, thereby extracting a large amount of thrombotic material. Follow-up angiography revealed resolution of the proximal LAD thrombus, but the distal LAD remained occluded due to a large residual thrombus burden. A 3 × 12-mm Maverick® balloon catheter (Boston Scientific Corporation; Natick, Mass) was then inflated to 6 atm on 3 occasions, but this had no effect on the distal LAD occlusive thrombus. The balloon was then inflated to 2 atm, and the thrombus was moved as far distally as possible, into the apical LAD. Follow-up angiography revealed a persistent thrombotic occlusion of the apical LAD, but the remainder of the coronary artery system was without disease (Fig. 3). At the conclusion of the case, the patient was pain free, with significant improvement of his ST elevations.
The patient was then transported to the cardiac care unit, pain free and in a hemodynamically stable condition; the eptifibatide infusion was continued (for a total of 18 hr), and an unfractionated-heparin infusion was added. An angiotensin-converting enzyme inhibitor, a β-blocker, aspirin, and an HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitor were also initiated. The patient met the diagnostic criteria for a myocardial infarction with a peak troponin I level of 56 ng/mL and a peak creatine kinase level of 2,160 U/L (MB fraction, 245 ng/mL). These peak values were obtained approximately 24 hours after the initial laboratory studies. His hospital course was unremarkable except for transient pericarditis, which was successfully treated with higher-dose aspirin therapy. Transthoracic echocardiography performed before his discharge from the hospital revealed overall preserved left ventricular systolic function with left ventricular ejection fraction visually estimated to be 0.55 to 0.60, severe apical hypokinesis, and a small pericardial effusion. Spontaneous echocardiographic contrast was present in the apex, without evidence of thrombus. Additional laboratory assessment included a lipid profile and evaluation for a hypercoagulable state, the results of which were within normal limits. The incidental finding of hemoglobin C trait, which is not known to be associated an increased risk of thrombosis, was discovered in the course of the patient's extensive laboratory evaluation. He was discharged from the hospital on warfarin therapy (thromboembolic prophylaxis in consideration of his apical myocardial infarction), aspirin, metoprolol tartrate, lisinopril, and atorvastatin. At follow-up, the patient had returned to full activities and had remained asymptomatic. Follow-up echocardiography revealed normal left ventricular function, with resolution of his apical hypokinesis.
This active, healthy young man experienced an acute myocardial infarction in the absence of any identifiable cardiovascular risk factors. Coronary angiography revealed thrombotic occlusion of the LAD in the absence of underlying atherosclerotic disease, coronary artery dissection, or active coronary artery spasm. Laboratory evaluation revealed no findings consistent with a hypercoagulable state, nor was there other evidence of systemic thromboembolic disease. Although we do not have toxicologic evidence confirming the absence of illicit drug use in our patient, he is an active-duty service member of the United States Navy who is required to undergo random drug screenings at least 3 to 4 times annually, and he had no reported history of abnormal urinalyses in the period leading up to his myocardialinfarction. While the cause of the patient's thrombus remains uncertain, it is plausible that the thrombus developed as a result of synephrine-induced coronary arterial spasm. Spasm-induced thrombus formation incoronary arteries has been demonstrated in animal mod-els and reported in several case studies.5
The well-publicized FDA ban, in 2004, on the sale of weight-loss products containing ephedrine alkaloids concluded almost a decade of governmental research into the safety of sympathomimetic agents in nonprescription products. Cited in the FDA's official report are statistics from the U.S. General Accounting Office documenting 92 reported serious adverse events (myocardial infarction, cerebrovascular accident, seizure, and death), one third of which occurred in patients younger than 30 years of age.4 The FDA report also referred to a RAND study that indicated the presence of other, less severe side effects, including palpitations, psychological symptoms, gastrointestinal symptoms, and autonomic hyperactivity (tremor/insomnia), all of which were enhanced by concomitant use of other stimulants.4 This investigation determined that ephedrine alkaloids constitute an “unreasonable risk” for most advertised uses, on the basis of data linking their use to increased risk of stroke, myocardial infarction, seizure, and death.4 This decision received considerable attention in the media due to the popularity of these products and to the adverse events in young athletes who took these weight-loss supplements. Since the FDA's ban on ephedra, new “ephedra-free” products have emerged, many of which contain sympathomimetic agents closely related to ephedrine, although not strictly in the same class. This chemical difference exempts them from the FDA legislation, which currently applies only to alkaloids related to, or derived from, ephedrine.
Ephedrine is a plant derivative that agonizes α- and β-adrenergic receptors3,6,7 in the heart and blood vessels, causing peripheral vasoconstriction and increased heart rate. This can have dramatic functional effects on the heart, because increased afterload and heart rate result not only in greater myocardial oxygen demand but in decreased diastolic filling and supply of oxygen to myocytes. Synephrine is an α- and β-adrenergic agonist derived from the herb “bitter orange;” it has sympathomimetic and structural similarities to ephedra and ephedrine alkaloids (Fig. 4).1,7 Despite their pharmacologic similarity to ephedra, the cardiovascular effects of synephrine have not yet been studied as extensively as those of ephedra.1 Case reports do exist of ischemic cerebrovascular accident, myocardial infarction, and unremitting tachycardia in association with synephrine use, but confounding factors exist in many of these reports.1,8 The Canadian Health Department reports that, from 1 January 1998 through 28 February 2004, it received 16 reports of adverse cardiovascular events—including tachycardia, cardiac arrest, ventricular fibrillation, and syncope—in suspected association with the use of products containing bitter orange or synephrine.6
Before the FDA ban on ephedra, popular weight-loss supplements often advertised use of the “ECA stack” (ephedrine, caffeine, and aspirin), which was alleged to stimulate the metabolism and increase fat-burning. Nutrex Lipo-6x is a newer, ephedra-free supplement that uses synephrine, yohimbe, and phenylethylamine as a variation on the ECA stack. Yohimbe is an extract from the West African yohimbe tree that has been used for purposes ranging from aphrodisia to hallucinogenesis. The active compound is yohimbine, a chemical classified as an α2-adrenergic antagonist.7 Paradoxically, reported adverse reactions include both hypotension and hypertension, as well as generalized weakness.7 Yohimbine can cause adverse reactions with other chemicals acting on α2-adrenergic receptors, such as clonidine. Phenylethylamine is a selective inhibitor of MAO-B that (in common with yohimbine) has been shown to cause hypotension and hypertension. Phenylethylamine-induced hypotension is primarily orthostatic and is thought to be caused by gradual displacement of norepinephrine from storage vesicles.7 Hypertension in this instance is similar to the effect seen with phenelzine and tranylcypromine when tyramine-containing foods are ingested concurrently.8 Caffeine is a well known and commonly used neurostimulant. The mechanism of action is thought to be direct adenosine receptor stimulation, in addition to the effects on monoamine neurotransmitters.2,7 Moreover, caffeine is a cAMP phosphodiesterase inhibitor and can also cause the release of intracellular calcium stores.7 Documented adverse cardiovascular effects include tachycardia, extrasystoles, increased stroke volume, and possibly other arrhythmias.2 Caffeine may also enhance the inotropic effect of β-adrenergic agents.2 Caffeine has been shown to directly stimulate cardiac function while dilating blood vessels and appears to have only mild effects on blood pressure.2
Although it is not possible to determine definitively the cause of our patient's thrombotic myocardial infarction, the most likely cause in the absence of any other identifiable risk factors is coronary artery spasm. Although the nutritional supplement in question, Nutrex Lipo-6x, contains a variety of sympathomimetic and stimulant compounds, the most likely culprit for the induction of coronary artery spasm is synephrine, consequent to its structural and pharmacologic similarities to ephedra. Our case highlights the potential health hazards associated with athletic-performance-enhancing and weight-reduction supplements that contain sympathomimetic compounds similar to ephedra. In light of these facts, as well as the empiric risk of synergism in the above-mentioned agents, we believe that performance-enhancement use was the precipitant of this patient's cardiac event, and we believe that greater FDA involvement in the regulation of such supplements is warranted.
Address for reprints: John E. Thomas, MD, Department of Medicine (Cardiology), Walter Reed Army Medical Center, 6900 Georgia Ave. NW, Washington, DC 20307
Disclosure statement: The views expressed in this article reflect the opinions of the authors only and not the official policy of the United States Army, United States Navy, or the Department of Defense. No personal or financial support or author involvement with any organization(s) with financial interest in the subject matter, or any actual or potential conflict of interest, is present with regard to any of the above-named authors.