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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.
      ECG (electrocardiography), FDA (Food and Drug Administration), RCA (right coronary artery)
      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.
      • Preuss HG
      • DiFerdinando D
      • Bagchi M
      • Bagchi D
      Citrus aurantium as a thermogenic, weight-reduction replacement for ephedra: an overview.
      • Samenuk D
      • Link MS
      • Homoud MK
      • et al.
      Adverse cardiovascular events temporally associated with Ma Huang, an herbal source of ephedrine.
      • Haller CA
      • Benowitz NL
      Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
      Consequently, in February 2004 the Food and Drug Administration (FDA) prohibited the sale of dietary supplements containing ephedra.
      • Food and Drug Administration, Health and Human Services
      Final rule declaring dietary supplements containing ephedrine alkaloids adulterated because they present an unreasonable risk: final rule.
      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.
      • Jordan S
      • Murty M
      • Pilon K
      Products containing bitter orange or synephrine: suspected cardiovascular adverse reactions.
      To our knowledge, we present the first case of variant angina associated with the use of bitter orange in a dietary supplement.

      REPORT OF A CASE

      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.
      Figure thumbnail gr1
      Figure 1During an anginal event, telemetry revealed ST-segment elevation with runs of nonsustained ventricular tachycardia and episodes of heart block.
      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).
      Figure thumbnail gr2
      Figure 2Electrocardiogram obtained after the administration of aminophylline shows marked ST-segment elevation in the inferior and lateral leads (top). Electrocardiogram changes completely resolved after the patient was given 1 sublingual nitroglycerin tablet (bottom).
      Aminophylline is known to trigger vasospasm in variant angina when used to reverse dipyridamole-induced coronary arteriolar dilation.
      • Picano E
      • Lattanzi F
      • Masini M
      • Distante A
      • L'Abbate A
      Aminophylline termination of dipyridamole stress as a trigger of coronary vasospasm in variant angina.
      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.

      DISCUSSION

      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.
      • Ricci 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.
      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.
      • Haller CA
      • Benowitz NL
      Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
      CortiSlim is an “ephedra-free” weight-loss supplement that contains bitter orange (Table 1). 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.
      • Fugh-Berman A
      • Myers A
      Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: current status of clinical and basic research.
      In animal studies, synephrine caused ventricular arrhythmias, increased cardiac output, and vasoconstriction.
      • Hofstetter R
      • Kreuder J
      • von Bernuth G
      The effect of oxedrine on the left ventricle and peripheral vascular resistance [in German].
      • Zhao 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.
      Synephrine can induce hypertension in humans and can exacerbate coronary spasm in tobacco smokers.
      • Hofstetter R
      • Kreuder J
      • von Bernuth G
      The effect of oxedrine on the left ventricle and peripheral vascular resistance [in German].
      • Keogh AM
      • Baron DW
      Sympathomimetic abuse and coronary artery spasm.
      Bitter orange can increase heart rate via indirect β-sympathomimetic activity and can trigger positive inotropic activity.
      In portal hypertensive rats, bitter orange peel extract decreased portal pressure and elevated arterial blood pressure.
      • Huang YT
      • Wang GF
      • Chen CF
      • Chen CC
      • Hong CY
      • Yang MC
      Fructus aurantii reduced portal pressure in portal hypertensive rats.
      Bitter orange has now been identified as a cause of resistant hypertension in humans.
      • Chobanian 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].
      Another report has linked the use of a bitter orange-containing diet product to an acute lateral wall myocardial infarction.
      • Nykamp DL
      • Fackih MN
      • Compton AL
      Possible association of acute lateral-wall myocardial infarction and bitter orange supplement.
      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.
      • Jordan S
      • Murty M
      • Pilon K
      Products containing bitter orange or synephrine: suspected cardiovascular adverse reactions.
      The cardiovascular risks of bitter orange may be increased in patients with preexisting cardiovascular problems.
      Table 1Ingredients in CortiSlim
      IngredientAmount per serving (1 capsule) (mg)
      Vitamin C (calcium ascorbate)100
      Calcium (calcium carbonate and ascorbate)150
      Chromium polynicotinate50
      Cortiplex155
       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% synephrine
      Insutrol16.5
       Banaba leaf extract (Lagerstroemia speciosa), 1% corosolic acid
       Vanadyl sulfate (5 μg vanadium)
      Inert ingredients: gelatin, microcrystalline cellulose, water, silicon dioxide, magnesium stearate
      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.
      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.
      • Haller CA
      • Benowitz NL
      • Jacob III, P
      Hemodynamic effects of ephedra-free weight-loss supplements in humans.
      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).
      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.
      • De Smet PA
      Herbal remedies.
      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 synephrine
      • Haller CA
      • Benowitz NL
      • Jacob III, P
      Hemodynamic effects of ephedra-free weight-loss supplements in humans.
      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.
      • De Smet PA
      Herbal remedies.
      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.
      • Naranjo CA
      • Busto U
      • Sellers EM
      • et al.
      A method for estimating the probability of adverse drug reactions.
      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.

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        Adverse cardiovascular events temporally associated with Ma Huang, an herbal source of ephedrine.
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        Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
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        Hemodynamic effects of ephedra-free weight-loss supplements in humans.
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