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Variant Angina Associated With Bitter Orange in a Dietary Supplement

2006; Elsevier BV; Volume: 81; Issue: 4 Linguagem: Inglês

10.4065/81.4.545

1942-5546

Christopher A. Gange, Christopher Madias, Erika Felix‐Getzik, Andrew Weintraub, N.A. Mark Estes,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

The Food and Drug Administration has banned the sale of ephedrine-based weight-loss products because of their association with many cardiovascular adverse effects. Bitter orange is now being used as a stimulant in "ephedra-free" weight-loss supplements but was recently implicated in adverse cardiovascular sequelae. To our knowledge, this report describes the first case of variant angina associated with bitter orange in a dietary supplement. The Food and Drug Administration has banned the sale of ephedrine-based weight-loss products because of their association with many cardiovascular adverse effects. Bitter orange is now being used as a stimulant in "ephedra-free" weight-loss supplements but was recently implicated in adverse cardiovascular sequelae. To our knowledge, this report describes the first case of variant angina associated with bitter orange in a dietary supplement. Excess weight is among the most common health problems in the United States, and failure to control weight with diet and exercise alone leads many Americans to use commercial weight-loss products. Although ephedra has become a popular weight-loss supplement, many studies have linked it to adverse reactions, especially cardiovascular sequelae.1Preuss HG DiFerdinando D Bagchi M Bagchi D Citrus aurantium as a thermogenic, weight-reduction replacement for ephedra: an overview.J Med. 2002; 33: 247-264PubMed Google Scholar, 2Samenuk D Link MS Homoud MK et al.Adverse cardiovascular events temporally associated with Ma Huang, an herbal source of ephedrine.Mayo Clin Proc. 2002; 77: 12-16Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 3Haller CA Benowitz NL Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.N Engl J Med. 2000; 343: 1833-1838Crossref PubMed Scopus (809) Google Scholar Consequently, in February 2004 the Food and Drug Administration (FDA) prohibited the sale of dietary supplements containing ephedra.4Food and Drug Administration, Health and Human Services Final rule declaring dietary supplements containing ephedrine alkaloids adulterated because they present an unreasonable risk: final rule.Fed Regist. 2004; 69: 6787-6854PubMed Google Scholar In response, many companies are now marketing "ephedra-free" products. However, these supplements can contain other stimulants that might be just as dangerous. A common ingredient of such supplements is bitter orange, which contains the stimulant agents synephrine, octopamine, and N-methyltyramine. Health Canada has received 16 reports on products containing bitter orange or synephrine that were implicated in cardiovascular adverse reactions.5Jordan S Murty M Pilon K Products containing bitter orange or synephrine: suspected cardiovascular adverse reactions.CMAJ. 2004; 171: 993-994PubMed Google Scholar To our knowledge, we present the first case of variant angina associated with the use of bitter orange in a dietary supplement. A 57-year-old man developed left-sided chest pressure with radiation to the jaw, shortness of breath, and diaphoresis while at rest, which resolved after 10 minutes. He presented to the emergency department of another hospital; his heart rate was 77 beats/min, blood pressure was 141/84 mm Hg, and remaining vital signs were normal. The patient weighed 93.4 kg and had a body-mass index of 29.5 kg/m2 (body mass index is calculated as weight in kilograms divided by the square of height in meters). Physical examination findings were normal. Electrocardiography (ECG) showed no abnormalities. He was admitted to a telemetry unit. The patient had history of hypertriglyceridemia and gastroesophageal reflux disease, as well as a 60-pack-year history of smoking, having quit 7 years previously. He reported drinking 3 to 4 alcoholic beverages at night but used no illicit drugs. Medications included fenofibrate, omeprazole, aspirin, a multivitamin, vitamin B complex, and vitamin E. For the past 35 days, the patient had been taking the weight-loss supplement CortiSlim, 1 tablet twice daily, with no identifiable adverse effects or noted weight change; the last dose he had taken was in the morning before this episode. Seventeen hours after admission, the patient's chest pressure returned but responded to sublingual administration of 3 nitroglycerin tablets. Four hours later, while the patient was brushing his teeth, the symptoms recurred. Telemetry revealed ST-segment elevation in leads II and III in association with episodes of complete heart block and runs of nonsustained ventricular tachycardia (Figure 1). A nitroglycerin drip was initiated, and he was transferred to our facility for cardiac catheterization. On admission to our hospital, the patient was asymptomatic. The ECG was normal. A temporary pacing wire was placed, and coronary angiography revealed right dominance, a 70% tubular mid left anterior descending lesion, and a 50% discrete mid circumflex lesion. The right coronary artery (RCA) showed no lesions. Fractional flow reserve after high-dose adenosine infusion (180 μg/kg per minute) was 0.86 across the left anterior descending lesion, making it unlikely as the origin of the patient's symptoms. Despite the full patency of the RCA, ischemia in its distribution was suggested by the ST-segment elevations in the inferior leads and accompanying conduction abnormalities observed earlier. A transthoracic echocardiogram revealed normal valves, normal atrial and ventricular size and function, and an ejection fraction of 55%. The patient remained asymptomatic with no arrhythmia during the night. The troponin I level was mildly elevated at 0.34 ng/mL (reference range,<.10 ng/mL) the following morning and peaked at 0.44 ng/mL that afternoon. The nitroglycerin drip was discontinued. It was suspected that the patient was experiencing variant angina. During a dipyridamole-induced stress test the following morning, he developed mild chest pressure but there were no ECG changes. After infusion of 125 mg of aminophylline, the study was terminated. At that point, the patient's chest-pressure syndrome recurred with an associated 3-mm ST-segment elevation in leads II and III and aVF as well as 2-mm ST-segment elevation in leads V3 through V6. The patient's symptoms and ECG findings responded fully to 0.4 mg of sublingual nitroglycerin after 2 minutes (Figure 2). Aminophylline is known to trigger vasospasm in variant angina when used to reverse dipyridamole-induced coronary arteriolar dilation.6Picano E Lattanzi F Masini M Distante A L'Abbate A Aminophylline termination of dipyridamole stress as a trigger of coronary vasospasm in variant angina.Am J Cardiol. 1988; 62: 694-697Abstract Full Text PDF PubMed Scopus (33) Google Scholar Nuclear imaging during the stress portion of the test revealed a small, mild inferolateral reversible defect and a small, mild septal reversible defect. The left ventricle showed normal wall motion and an estimated ejection fraction of 62%. The patient was treated for variant angina with a calcium channel blocker. A statin and an angiotensin-converting enzyme inhibitor were initiated, and aspirin use was continued. The patient was instructed to discontinue use of the weight-loss supplement. After discharge, the patient stopped taking the dietary supplement and remained symptom free for approximately 4 months. However, he then began to develop chest pain, and his cardiologist prescribed a nitroglycerin patch and increased the dose of the calcium channel blocker. These measures relieved the patient's symptoms, and he has not undergone any further work-up for his recurrent chest pain syndrome. This patient's presentation was typical of variant angina involving the RCA. Coronary spasm, largely triggered by α-adrenergic tone, is the cause of variant angina.7Ricci DR Orlick AE Cipriano PR Guthaner DF Harrison DC Altered adrenergic activity in coronary spasm: insight into mechanism based on study of coronary hemodynamics and the electrocardiogram.Am J Cardiol. 1979; 43: 1073-1079Abstract Full Text PDF PubMed Scopus (123) Google Scholar Inasmuch as our patient's cluster of variant angina occurred several weeks after he initiated use of CortiSlim, we suggest a temporal pathogenic link between these events. Vasospasm is viewed as the mechanism of myocardial infarction and myocarditis associated with ephedrine use.3Haller CA Benowitz NL Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.N Engl J Med. 2000; 343: 1833-1838Crossref PubMed Scopus (809) Google Scholar CortiSlim is an "ephedra-free" weight-loss supplement that contains bitter orange (Table 1).8CortiSlim® [ingredients].Available at: www.fitnessone.com/product_info.php/products_id/356Google Scholar Bitter orange peel extract contains alkaloids that are structurally similar to ephedrine, epinephrine, and norepinephrine, including the α-adrenergic agonists synephrine, octopamine, and N-methyltyramine.9Blumenthal M The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. American Botanical Council, Austin, Tex1998: 89-90Google Scholar, 10Fugh-Berman A Myers A Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: current status of clinical and basic research.Exp Biol Med (Maywood). 2004; 229: 698-704PubMed Google Scholar In animal studies, synephrine caused ventricular arrhythmias, increased cardiac output, and vasoconstriction.11Hofstetter R Kreuder J von Bernuth G The effect of oxedrine on the left ventricle and peripheral vascular resistance [in German].Arzneimittelforschung. 1985; 35: 1844-1846PubMed Google Scholar, 12Zhao XW Li JX Zhu ZR Sun DQ Liu SC Anti-shock effects of synthetic effective compositions of Fructus aurantii immaturus: experimental study and clinical observation.Chin Med J (Engl). 1989; 102: 91-93PubMed Google Scholar Synephrine can induce hypertension in humans and can exacerbate coronary spasm in tobacco smokers.11Hofstetter R Kreuder J von Bernuth G The effect of oxedrine on the left ventricle and peripheral vascular resistance [in German].Arzneimittelforschung. 1985; 35: 1844-1846PubMed Google Scholar, 13Keogh AM Baron DW Sympathomimetic abuse and coronary artery spasm.Br Med J. 1985; 291: 940Crossref PubMed Google Scholar Bitter orange can increase heart rate via indirect β-sympathomimetic activity and can trigger positive inotropic activity.14Blumenthal M Herbal Medicine: Expanded Commission E Monographs. Integrative Medicine Communications, Newton, Mass2000: 287-289Google Scholar In portal hypertensive rats, bitter orange peel extract decreased portal pressure and elevated arterial blood pressure.15Huang YT Wang GF Chen CF Chen CC Hong CY Yang MC Fructus aurantii reduced portal pressure in portal hypertensive rats.Life Sci. 1995; 57: 2011-2020Crossref PubMed Scopus (50) Google Scholar Bitter orange has now been identified as a cause of resistant hypertension in humans.16Chobanian AV Bakris GL Black HR Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, National Heart, Lung, and Blood Institute, National High Blood Pressure Education Program Coordinating Committee et al.Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [published correction appears in JAMA. 2003;290:197].JAMA. 2003; 289: 2560-2572Crossref PubMed Scopus (16539) Google Scholar Another report has linked the use of a bitter orange-containing diet product to an acute lateral wall myocardial infarction.17Nykamp DL Fackih MN Compton AL Possible association of acute lateral-wall myocardial infarction and bitter orange supplement.Ann Pharmacother. 2004; 38: 812-816Crossref PubMed Scopus (80) Google Scholar Sixteen reports of cardiovascular events associated with bitter orange use were reported to Health Canada during a 6-year period, which included tachycardia, cardiac arrest, ventricular fibrillation, transient collapse, and syncope.5Jordan S Murty M Pilon K Products containing bitter orange or synephrine: suspected cardiovascular adverse reactions.CMAJ. 2004; 171: 993-994PubMed Google Scholar The cardiovascular risks of bitter orange may be increased in patients with preexisting cardiovascular problems.Table 1Ingredients in CortiSlim8CortiSlim® [ingredients].Available at: www.fitnessone.com/product_info.php/products_id/356Google ScholarIngredientAmount per serving (1 capsule) (mg)Vitamin C (calcium ascorbate)100Calcium (calcium carbonate and ascorbate)150Chromium polynicotinate50Cortiplex155 Magnolia bark extract (Magnolia officinalis), 1.5% honokiol Beta-sitoserol Suntheanine (100% L-theanine)Leptiplex125 Green tea leaf extract (Camellia sinensis), 50% epigallocatechin gallate Bitter orange peel extract (Citrus aurantium), 5% synephrineInsutrol16.5 Banaba leaf extract (Lagerstroemia speciosa), 1% corosolic acid Vanadyl sulfate (5 μg vanadium)Inert ingredients: gelatin, microcrystalline cellulose, water, silicon dioxide, magnesium stearate Open table in a new tab The risk of drug interactions also needs to be considered. The furocoumarins bergamottin and dihydroxybergamottin, known cytochrome P-450 3A4 inhibitors contained in grapefruit, are also found in bitter orange fruit and juice; unwanted interactions with medications that are metabolized via the cytochrome P-450 3A4 pathway might ensue.9Blumenthal M The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. American Botanical Council, Austin, Tex1998: 89-90Google Scholar Additional drug interactions might be experienced when bitter orange peel is combined with other stimulant agents (eg, caffeine, pseudoephedrine, etc). A recent prospective, blinded study concluded that dietary supplements containing bitter orange in combination with other stimulants raised systolic and diastolic blood pressure as well as heart rate in healthy adults.18Haller CA Benowitz NL Jacob III, P Hemodynamic effects of ephedra-free weight-loss supplements in humans.Am J Med. 2005; 118: 998-1003Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar Green tea is a caffeine-containing agent that is often used as a stimulant in weight-loss agents. Added to bitter orange, this combination might increase the risk of adverse cardiovascular events. Notably, CortiSlim also contains green tea (Table 1).8CortiSlim® [ingredients].Available at: www.fitnessone.com/product_info.php/products_id/356Google Scholar A limitation to our report is the absence of a toxicological evaluation of the specific supplement because it was not available for us to study. It is important to acknowledge that dietary supplements have been shown to contain contaminants as well as contents in amounts that vary from what their labels report.19De Smet PA Herbal remedies.N Engl J Med. 2002; 347: 2046-2056Crossref PubMed Scopus (559) Google Scholar In addition, our patient experienced a delay of approximately 17 hours between his variant angina attack and the last known ingestion of the supplement containing bitter orange. After factoring in the 3 hour half-life of synephrine18Haller CA Benowitz NL Jacob III, P Hemodynamic effects of ephedra-free weight-loss supplements in humans.Am J Med. 2005; 118: 998-1003Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar and the steady-state concentrations, based on pharmacokinetics, the patient's anginal symptoms occurred within the expected 5 to 7 half-life time frame. However, our clinical observations suggest more than just a single-step interaction between synephrine and angina. As mentioned previously, bitter orange contains numerous stimulant compounds, making it difficult to estimate their collective pharmacodynamic half-life. Giventhat some of these compounds may act synergistically or that there may be unidentified metabolites involved, it is possible that the pharmacological effects associated with vasospasm could persist even longer. The fact that our patient experienced further chest pain 4 months after discontinuing use of the dietary supplement could imply that the sentinel vasospasm event was due to chance and not from bitter orange ingestion. However, it more likely demonstrates that the patient was at high risk for cardiovascular events and that his first episodes of variant angina were due to consuming a dietary supplement that can induce such events. The Dietary Supplement Health and Education Act of 1994 allows companies to sell dietary products without first being required to prove their effectiveness or safety to the FDA.19De Smet PA Herbal remedies.N Engl J Med. 2002; 347: 2046-2056Crossref PubMed Scopus (559) Google Scholar In addition, unlike regulations imposed on prescription drug companies, these companies have no obligation to inform the FDA of adverse events reported with the use of their products. Ephedra is now prohibited from being sold in the United States because of its association with adverse cardiovascular reactions and death. Application of the Naranjo probability scale demonstrated a possible association between the use of the bitter orange-containing product and the variant angina experienced by our patient.20Naranjo CA Busto U Sellers EM et al.A method for estimating the probability of adverse drug reactions.Clin Pharmacol Ther. 1981; 30: 239-245Crossref PubMed Scopus (8419) Google Scholar This case adds to the list of cardiovascular events that have been linked to bitter orange. The public might incorrectly assume that these "ephedra-free" substances are safe, but dietary supplements that contain bitter orange might pose serious health risks. Further research to assess the safety of bitter orange is warranted.