ORIGINAL ARTICLE

Vitamins, Supplements, Herbal Medicines, and Arrhythmias

Mina K. Chung, MD

Abstract: Nutritional and herbal supplements may have harmful or benecial effects on arrhythmias. Potential supplements that may have antiarrhythmic activity include omega-3 polyunsaturated fatty acids (N-3 PUFA), coenzyme Q10, and carnitine. Clinical studies show that N-3 PUFA or sh oil supplementation appears to reduce mortality and sudden death. Coenzyme Q10, used in treatment of heart failure, and carnitine and its derivatives may have benecial effects on arrhythmias, although clinical studies have been limited. Antioxidant supplements may be benecial, but large studies with vitamin E have been disappointing in that it does not reduce mortality. Correction of electrolyte disturbances has been long advised and magnesium supplementation has been benecial in the treatment of torsades de pointes and in some studies after cardiac surgery. However, routine electrolyte supplementation with empiric potassium or magnesium in non-decient patients has not been convincingly benecial. Several herbal supplements have also been promoted to have antiarrhythmic activity. However, clinical studies are lacking to support routine use of these herbal medications. In addition, some herbal supplements may cause serious proarrhythmia, and many supplements signicantly interact with warfarin and digoxin. Key Words: arrhythmias, herbal medicine, vitamins, electrolytes, supplements (Cardiology in Review 2004;12: 73 84)

ELECTROLYTES Potassium
Hypokalemia has been associated with increases in arrhythmias, including atrial and ventricular ectopy, tachycardias, and prolonged QT-associated torsades de pointes. A study of perioperative hypokalemia reported that serum potassium levels 3.5 mmol/L increased perioperative arrhythmias after coronary artery bypass surgery.1 Hypokalemia is a common sequela of diuretic use and can also occur in the user of licorice. Supplementation in potassium-decient patients with arrhythmias is advised to maintain a potassium concentration of 4.0 mmol/L. Whether potassium supplementation reduces arrhythmia or sudden death risk perioperatively or chronically in nondecient patients has not been studied.

Magnesium
As in hypokalemia, hypomagnesemia has been associated with increased arrhythmias, including postoperatively or in the setting of congestive heart failure.2,3 Loop and thiazide-type diuretics can cause magnesium loss. The benets of magnesium supplementation in the treatment of prolonged QT-induced torsades de pointes have been well established. In this condition, treatment often includes 1 to 2 g magnesium sulfate given intravenously. Magnesium has been reported to increase ventricular brillation threshold and prolong sinus node refractoriness and atrioventricular nodal conduction. However, although many studies have reported that magnesium supplementation decreased arrhythmias after cardiac surgery,4,5 myocardial infarction,6 10 or congestive heart failure,1113 other studies have produced disappointing results.14 16 In ISIS-4,17 58,050 patients with suspected acute myocardial infarction were randomized to oral captopril versus placebo, oral mononitrate versus placebo, and 24 hours of intravenous magnesium (8 mmol followed by 72 mmol) versus open control. Magnesium failed to reduce mortality. Nevertheless, subsequent studies have suggested that early rather than later intravenous magnesium could be benecial.18 20 A large randomized trial of early intravenous magnesium in acute myocardial infarction in 6.213 patients showed no effect on 30 day mortality.21 In summary, acute intravenous magnesium has been an established treatment of treatment of torsades de pointes. It could have some benets in reducing arrhythmias after car-

ecause vitamin and herbal supplement use has grown signicantly in the general population, it is of increasing importance to investigate and assess the potential impact of these supplements on cardiac arrhythmias. Some supplements can have proarrhythmic effects either alone or in combination with conventionally prescribed medications. However, some agents might prove to be benecial, and several of our more effective conventional antiarrhythmic agents have developed from herbal/plant sources.

From the Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio. Reprints: Mina K. Chung, MD, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk F-15, Cleveland, OH 44195.chungm@ccf.org Copyright 2004 by Lippincott Williams & Wilkins ISSN: 1061-5377/04/1202-0073 DOI: 10.1097/01.crd.0000091839.22076.f4

Cardiology in Review Volume 12, Number 2, March/April 2004

73

Chung

Cardiology in Review Volume 12, Number 2, March/April 2004

diac surgery. However, intravenous magnesium has not been shown to reduce mortality after acute myocardial infarction remain under study.

VITAMINS Vitamin C
Vitamin C, or ascorbate, is an antioxidant that may have value in some situations in which oxidative stress might be arrhythmogenic. Atrial brillation is a common arrhythmia in which perpetuation of the arrhythmia could be promoted by electrophysiological and structural remodeling.22 Early changes during atrial brillation or rapid atrial pacing stimulation include a shortening of atrial refractory period (ERP).23 Such shortening of ERP predisposes the atria to reentrant arrhythmias, and longer durations of rapid atrial stimulation lead to greater susceptibility to perpetuation of atrial brillation.23 Atrial tissue from patients with chronic atrial brillation also show evidence of increased oxidative stress and peroxynitrite formation.24,25 Ascorbate has been shown to potentially attenuate the electrophysiological changes and oxidative stress induced during rapid atrial rates. In a dog model of rapid atrial pacing, atrial ERP shortened, tissue ascorbate levels were reduced, and protein nitration, a marker of peroxynitrite formation, was increased.25 Oral treatment with ascorbate, an antioxidant and peroxynitrite decomposition catalyst, attenuated pacing-induced atrial ERP shortening, tissue ascorbate level reduction, and the increase in peroxynitrite formation. Vitamin C was used in a non-randomized pilot study for the prevention of postoperative atrial brillation. Atrial brillation is a common complication occurring after cardiac surgery with an incidence of 20% to 50%. Surgery is a potent stimulator of oxidative and inammatory stress. In 43 patients given 2 g ascorbic acid the night before coronary artery bypass surgery, followed by 500 mg doses twice daily for up to 5 days after surgery, the incidence of postoperative atrial brillation appeared to be reduced.25 Patients treated with ascorbate had a 16.3% incidence of atrial brillation, compared with 34.9% in age- and gender-matched control patients not given vitamin C. The proposed mechanism is postulated to relate to a reduction in oxidative stress induced by cardiac surgery. A randomized, controlled trial is ongoing. The effect of chronic vitamin C use for nonpostoperative arrhythmias has not been established.

supplementation.2731 The GISSI-Prevenzione trial of 11324 patients surviving recent (3 months) myocardial infarction were assigned 1 g omega-3 polyunsaturated fatty acids daily, 300 mg vitamin E (synthetic alpha-tocopherol) daily, both, or placebo for 3.5 years. Treatment with omega-3 polyunsaturated fatty acids, but not vitamin E, signicantly lowered the risk of the combined primary end point of overall death, nonfatal myocardial infarction, and stroke.29 However, vitamin E reduced cardiovascular death by 20% and sudden death by 35%. The Heart Outcomes Prevention Evaluation (HOPE) study randomized 9541 patients with vascular disease or diabetes plus one other coronary risk factor to receive 400 IU vitamin E per day, 10 mg ramipril 10 per day, both, or placebo for a mean of 4.5 years.30 Vitamin E produced no signicant differences in myocardial infarction, stroke, or cardiovascular disease death. The Primary Prevention Project (PPP) randomized 4495 patients with one or more coronary risk factors to 100 mg aspirin per day, 300 mg vitamin E per 31 day, both, or placebo. Vitamin E produced no reduction in end points. With regard to the effect of vitamin E on arrhythmias, a small trial of vitamin E and selenium on heart failure and ventricular arrhythmias in patients with myocardial infarction showed no differences in ventricular arrhythmias as shown on long-term ECG.32 In summary, vitamin E does not appear to reduce overall or cardiovascular mortality. Except for a possible reduction in sudden death seen in the GISSI-Prevenzione trial, no other signicant data has been reported that indicates a benecial effect on arrhythmias from vitamin E.

SUPPLEMENTS WITH REPUTED BENEFITS IN ARRHYTHMIA SUPPRESSION Coenzyme Q10

Coenzyme Q10 (ubidecarenone, CoQ10, E-0216) has been used in the treatment of heart failure, mitochondrial disease, hypertension, angina, and arrhythmias.33 It is an antioxidant, free-radical scavenger, and membrane stabilizer. Coenzyme Q10 and its derivatives have been shown to reduce reperfusion arrhythmias in animal models, apparently related to prevention of phospholipase release of free fatty acids from phospholipids. In animal models, pretreatment with coenzyme Q10 or its derivatives reduced the incidence of reperfusion arrhythmias from 32% to none.34,35 Arrhythmia suppression effects from coenzyme Q10 has been studied in some clinical trials in humans. In a randomized, double-blind, placebo-controlled trial in 144 patients with acute myocardial infarction, coenzyme Q10 at 120 mg per day for 28 days reduced angina, improved poor ventricular function, and reduced total arrhythmias (9.5% versus 25.3% in placebo patients).36 In an observational, nonrandomized study of 50 to 150 mg oral daily coenzyme Q10 in 2664 patients with NYHA class II and III heart
2004 Lippincott Williams & Wilkins

Vitamin E
Vitamin E is also an antioxidant that has been studied for its potential ability to slow progression of atherosclerosis.26 Despite promising animal and early observational studies suggesting a protective effect for development of coronary heart disease and death from coronary disease, large-scale studies have reported disappointing results for vitamin E

74

Cardiology in Review Volume 12, Number 2, March/April 2004

Vitamins, Supplements, Herbal Medicines, and Arrhythmias

failure, clinical symptoms improved after 3 months, including arrhythmia in 63%.37 Coenzyme Q10 was also reported to reduce premature ventricular depolarizations on Holter monitoring in 22% (6 of 27) of patients with diabetes or hypertension but no clinical organic heart disease.38

mediary metabolites of fatty acids, such as long-chain acylcarnitines, accumulate and are arrhythmogenic.53 Whether carnitine supplementation will improve arrhythmias in these syndromes remains to be demonstrated.

Omega-3 Fatty Acids and Fish Oil Carnitine

Carnitine has an important role in long-chain fatty acid oxidation; it is a carrier in the transport of activated longchain fatty acids into the mitochondria where beta oxidation occurs.39 In hypoxia, beta-oxidation becomes the rate-limiting step in lipid oxidation.39,40 In ischemia, when fatty acid oxidation is limiting, long-chain fatty acids, which are toxic to cells, can accumulate. L-carnitine or propionyl L-carnitine may improve lipid oxidation in early ischemia or reperfusion and thereby reduce the toxic accumulation of these fatty acids. Carnitine also is involved in metabolism of branched chain amino acids, stabilization of cell membranes, and scavenging of free radicals.41 Carnitine and its derivatives may reduce ischemiainduced arrhythmias or arrhythmias from other conditions in which toxic long-chain acylcarnitines accumulate. L-carnitine and propionyl-L-carnitine can decrease intracellular accumulation of toxic metabolites during ischemia42 by improving fatty acid oxidation. This can lead to protection by carnitine or its derivatives of ischemic myocardial lipid membranes and protein enzymes and a reduction in ischemic or reperfusion associated ventricular arrhythmias, including ventricular brillation, as demonstrated in animal models.43 45 Another potential mechanism leading to a reduction in ischemic arrhythmias may be via an increase in glucose metabolism, increase in pyruvate, and subsequent adenosine triphosphate (ATP), leading to a decrease in the necrotic area that might predispose to ventricular arrhythmias.41,46 In humans, L-carnitine has been associated with reduction in ventricular arrhythmia frequency in patients with angina pectoris47 or acute myocardial infarction.48 Thus, carnitine may prove to be a promising therapy for ischemia or reperfusion-induced arrhythmias. Carnitine supplementation has also been studied for other arrhythmias. Only minimal electrophysiological changes detected after 30 mg/kg L-propionylcarnitine were given over 3 minutes with only a 5% shortening of sinus cycle length reported.49 Carnitine has been reported to decrease the incidence of supraventricular and ventricular arrhythmias during hemodialysis.50 In a cat model, thresholds for electrically induced atrial brillation were increased by 100 mg/kg intravenous carnitine.51 Another study reported a reduction in ventricular extrasystoles in hypertensive patients treated with 2 g oral L-carnitine per day.52 Carnitine supplementation may also be benecial in some genetic defects of fatty acid metabolism, particularly in defects of long-chain fatty acid transport across the inner mitochondrial membrane or other defects in which inter 2004 Lippincott Williams & Wilkins

Fish oil and omega-3 fatty acids (N-3 polyunsaturated fatty acids [N-3 PUFA]) have been demonstrated to have benecial effects on coronary heart disease prevention, mortality, and ventricular arrhythmias. Although N-6 fatty acids appear to be arrhythmogenic, N-3 series fatty acids appear to have antiarrhythmic effects. The n-6 fatty acids, particularly linoleic acid, can be elongated and desaturated to arachidonic acid, and then oxygenated through cyclooxygenase to 2-series prostaglandins and thromboxane, which have been shown to be arrhythmogenic, except for prostacyclin.54,55 In contrast, none of the 3-series cyclooxygenase products of eicosapentaenoic acid (EPA) were arrhythmogenic and, in fact, n-3 fatty acids appeared protective. Animal models have demonstrated the arrhythmogenic effects of long-chain saturated fatty acids and the antiarrhythmic effects of N-3 PUFA.56 Tuna sh oil supplementation reduced ventricular brillation during coronary artery occlusion and reperfusion in rats.57 In marmosets fed diets supplemented with PUFA-rich tuna sh oil (N-3 PUFA) or sunower seed oil (N-6 PUFA), ventricular brillation threshold after acute myocardial ischemia, induced by coronary artery occlusion, was reduced with PUFA.58 Fish oil was associated with a low incidence of sustained brillation. In a canine model of postinfarction sudden cardiac death, ischemic-induced ventricular brillation was prevented in up to 87% of dogs by n-3 PUFA and intravenous administration of the puried n-3 PUFA, docosahexaenoic acid (DHA), or EPA.59,60 This protective effect appears to be the result of a membrane-stabilizing effect with a reduction in membrane electrical excitability by suppression of L-type Ca (ICa-L) and voltage-dependent Na (INa) channel currents.61,62 N-3 PUFA prolongs the inactivated state of INa and shifts cells to more negative resting membrane potentials.63 65 These effects would be protective in ischemic areas in which the resting membrane potential is partially depolarized and closer to threshold. N-3 PUFA effects on ICa-L may include a decrease in Ca uxes, Ca overload, and triggered arrhythmias from afterdepolarizations.60,66 Several clinical studies have reported benecial effects of N-3 PUFA on mortality, sudden death, and arrhythmias. In a prospective, randomized, double-blind, placebo-controlled 16-week trial of sh (cod liver) oil versus placebo sunower seed oil in 79 patients with frequent premature ventricular complexes without overt structural heart disease, sh oil reduced PVCs by 70% in 44% of patients compared with 15% in the placebo group.67 The Diet and Reinfarction Trial (DART) randomized 2033 men after myocardial infarction to

75

Chung

Cardiology in Review Volume 12, Number 2, March/April 2004

receive advice on 1 of 3 diet strategies: 1) reduction in fat intake to 30% of total energy and increase in ratio of polyunsaturated to saturated fat; 2) increase in fatty sh intake to at least 2 200- to 400-g portions of fatty sh weekly or 1.5-g sh oil capsules; or 3) increase in cereal ber to 18 g daily.68 The fatty sh advice group had a 29% reduction in 2 year all-cause mortality compared with those who did not receive this advice. The GISSI-Prevenzione trial of 11,324 patients surviving recent (3 months) myocardial infarction were assigned 1 g N-3 PUFA daily, 300 mg vitamin E daily, both, or none.29 Patients treated with N-3 PUFA had a 20% decrease in total mortality and 45% reduction in sudden death. The Physicians Health Study69 reported that dietary sh and N-3 PUFA intakes were associated with a lower risk of sudden death among 20,551 U.S. male physicians completing a baseline questionnaire regarding sh consumption. Dietary sh intake was associated with a reduced risk of sudden death and total mortality. The threshold for the effect appeared to be at 1 sh meal per week. The multivariate relative risk of sudden death was 0.48 (52% lower risk) in males who consumed sh at least once per week compared with men who had sh less than monthly. A lower risk of sudden death was also seen when analyzed by any intake of n-3 PUFA. Blood levels of long-chain N-3 fatty acids, found in sh oil, were inversely correlated with risk of sudden death in apparently healthy men followed in the Physicians Health study.70 In this case-control substudy, 94 men who had sudden death as their rst manifestation of cardiovascular disease were compared with 184 men matched for age and smoking status. The relative risk of sudden death was significantly lower in subjects with levels in the third and fourth quartiles. Besides the large-scale studies noted here, other clinical studies have also reported signicant reductions in sudden cardiac death from n-3 PUFA.70 73 Omega-3 PUFA also increased heart rate variability in survivors of myocardial infarction randomized to sh oil or olive oil.74,75 A primary benecial effect of sh consumption and N-3 PUFA intake may be through a reduction in the risk of fatal arrhythmias. These ndings have motivated ongoing trials, including a randomized, placebo-controlled trial of sh oil compared with placebo, to look at the incidence of recurrent ventricular arrhythmias/shocks in patients who have ICDs and are at risk for sudden death.

Cardioactive Digoxin-Like Glycosides

Many plant sources of natural cardioactive glycosides with positive inotropic action have been identied.76 Digitoxin (derived from Digitalis purpurea [foxglove] or Digitalis lanata), and digoxin (derived from Digitalis lanata)76 have been used for treatment of congestive heart failure and for their sinus nodal and atrioventricular nodal-slowing effects. Digitalis has also been derived from Digitalis ambigua (yellow foxglove), Digitalis ferriginea (rusty foxglove), Digitalis grandiora, Digitalis lanata (yellow foxglove), and Digitalis lutea (straw foxglove). Common names include foxglove, purple foxglove, throatwort, fairy nger, fairy cap, ladys thimble, scotch mercury, lions mouth, witchs bells, dead mans bells, and wolly foxglove.77 Herbs containing cardiac glycosides or digoxin-like substances include76,78 Adonis vernalis and Adonis microcarpa (adonis, false hellebore, pheasants eye); Apocynum androsaemifolium and Apocynum cannabinum (dogbane, milkweed, wild ipecac, black Indian hemp); Asclepias tuberosa (pleurisy root), Asclepias curassavica (redheaded cotton bush), and Asclepias friticosa (balloon cotton); Calotropis precera (kings crown); Carissa spectabilis (wintersweet); Cerebra manghas (sea mango); Cheiranthus cheiri (Wallower); Convallaria majalis (lily of the valley, convallaria); Cryptostegia grandiora (rubber vine); Cystisus scoparius (broom); Digitalis ambigua (yellow foxglove); Digitalis ferriginea (rusty foxglove); Digitalis grandiora; Digitalis lanata (yellow foxglove); Digitalis lutea (straw foxglove); Digitalis purpurea (purple foxglove); Eleutherococcus senticosus (Siberian ginseng); Helleborus niger (black hellebore); Helleborus veridus; Leonurus cardiaca (motherwort); Nerium oleander (oleander); Scilla maritima (white squill); Scrophularia nodosa (gwort); Strophantus hispidus and kombe (strophanthus); Thevetia peruviana (yellow oleander); Urginea maritima (squill); and Uzarae radix (uzara root). Besides plant sources, a digitalis-like steroid, marinabufagenin, has been extracted from Bufo marinus (cane toad) venom76 and the Chinese toad Bufo bufo gargarizans cantor venom, which is contained in kyushin.78 Toxic reactions and overdoses have been frequently reported with these glycoside-containing herbs or supplements (see subsequently in this article). Because of their narrow therapeutic window, it is advisable to avoid use of these herbs and other nonstandard supplements for treatment of congestive heart failure or arrhythmias and instead use indicated conventional standardized digoxin preparations.

HERBAL SUPPLEMENTS
Conventional antiarrhythmic drugs that were discovered from herbs or plants include quinidine (a stereoisomer of quinine from cinchona bark), lidocaine, amiodarone (from Khellin, originally from the herb ammi visnaga), digoxin (foxglove), and atropine (atropa belladonna, or nightshade).

Herbs With Calcium Channel Antagonism

Extracts from the root of the Chinese herb Stephania tetrandra have been used to treat hypertension and have calcium channel-blocking activity similar to that of verapamil.76 Radix Stephaniae Tetrandrae (RST) extracts inhibit Ca inux and reperfusion arrhythmias. Tetrandrine and fanchinoline
2004 Lippincott Williams & Wilkins

76

Cardiology in Review Volume 12, Number 2, March/April 2004

Vitamins, Supplements, Herbal Medicines, and Arrhythmias

are 2 of the major components of the alkaloid extract. Tetrandrine blocks T and L calcium channels, inhibiting binding of diltiazem and methoxyverapamil to calcium channel-binding sites.79 RST extract and tetrandrine inhibited arrhythmias associated with myocardial infarction in animal studies, but without as much heart rate inhibition during ischemia as seen with verapamil.80 Tetrandrine has also been reported to decrease aldosterone production and have antineoplastic, immunosuppressive, and mutagenic effects.79 However, tetrandrine is one of the herbs potentially causing rapidly progressive renal failure (Chinese herb nephropathy), although many patients had been on a combination of herbs and stephania tetrandra could have also been misidentied.81 Nevertheless, it has also caused liver necrosis in dogs; the safe dosage in humans has not been established.79 Taxine, derived from English yew leaves (Taxus baccata L), has calcium channel blockade activity. Similar to verapamil, negative inotropic and chronotropic effects were reported on isolated atrium preparations with higher selectivity for the heart over vessel and intestine than verapamil.82 Uncaria rhynchophylla and amsonia elliptica contain indole alkaloids, which have electrophysiological effects in the heart with potency that could approximate that of ajmaline, an antiarrhythmic drug that is also an indole alkaloid. These herbs contain hirsutine, rhynchophylline, isorhynchophylline, and dihydrocorynantheine.83 These and beta-yohimbine isolated from amsonia elliptica have shown potential reduction in aconitine-induced arrhythmias in mice and ouabain-induced arrhythmias in guinea pigs.83 Hirsutine and dihydrocorynantheine affect action potentials of the sinoatrial node, the atria, and the ventricles, leading to negative chronotropic and antiarrhythmic actions. In sinoatrial preparations, these increase cycle length, decrease slope of phase 4 depolarization, and decrease maximum rate of rise and prolong action potential duration.84 In ventricular and atrial preparations, they decreased maximum rate of rise and prolonged action potential duration. Uncaria rhynchophylla has been reported to inhibit calcium channels, inhibit nicotineinduced dopamine release,79 stimulate endothelium-derived relaxing factor and/or nitric oxide release,85 and inhibit platelet aggregation.79 In the rat aorta, hirsutine appears to block Ca channel activity mainly through inhibition of the voltage-dependent Ca inux.86 Rhynchophylline exhibits Ltype Ca channel-blocking activity.87 Uncaria rhynchophylla has been used in Chinese traditional medicine to treat hypertension.76 However, clinical data establishing its safety and efcacy in humans is lacking.

Herbs With Activity Against Ischemic Arrhythmias and Free Radicals

Several herbs have been reported to be protective against ischemic and/or reperfusion-induced arrhythmias, particularly in animal models. Many of these have antioxi 2004 Lippincott Williams & Wilkins

dant, free-radical scavenging activity. These herbs include Crataegus species (hawthorn), gingko biloba, garlic, and angelica. However, few have been tested in clinical studies in humans. Crataegus species (Crataegus oxyacantha, Crataegus laevigata, and Crataegus monogyna; hawthorn, English hawthorn, haw, maybush, whitethorn) have been reported to have cardiovascular and antiarrhythmic effects. Crataegus leaves, owers, and fruits contain active oligomeric procyanins, catechins, avonoids, including hyperoside (vitexin, rhamnose) rutin, hyperoside and vitexin-rhamnoside, leucoanthocyanidins, and crataeguslactone (mixture of ursolic, oleanic, and crataegolic acids).76,77Animal studies suggest Crataegus extracts produce cAMP-independent inotropic effects, vasodilation, and antioxidant and antiinammatory effects. They can also inhibit formation of thromboxane A2.88 Crataegus oxycantha has been used as a cardiac tonic for angina, hypertension, arrhythmias, and congestive heart failure. Crataegus has positive inotropic and negative chronotropic effects, increases coronary perfusion, and has mild hypotensive effects.76,89 Crataegus extracts have been reported to reduce ischemia-induced ventricular arrhythmias.90,91 However, one study of long-term (8 weeks) Crataegus oxyacantha feeding in rats reported an aggravation of ischemia and reperfusioninduced arrhythmias that might have been the result of an increase in intracellular calcium concentration.92 Hawthorn extract has also been reported to prolong effective refractory periods and to have possible sympathomimetic-blocking activity.93 Crataegus can enhance activity of concomitant digoxin.76 A mechanism of action for the cardiac effects of Crataegus could involve 3,5-cyclic adenosine monophosphate phosphodiesterase inhibition.94 The antiarrhythmic capacity of Crataegus extract has been studied in some human clinical trials. In a study of 1011 patients with NYHA stage II heart failure, high-dose Crataegus extract WS 1442 (Crataegutt novo 450, 1 tablet twice per day) was tested in an observational study over 24 weeks.95 At the end of the monitoring period, improved ejection fraction, slower resting pulse, improved exercise tolerance test, fatigue, palpitations, and exercise dyspnea, and fewer patients with arrhythmias and ventricular extrasystoles at maximum exercise level were reported. Crataegus extract WS 1442 (2 450 mg per day) is being studied in a randomized, placebocontrolled, double-blind study (SPICE) of cardiac death, nonlethal myocardial infarction, and hospitalization resulting from progression of heart failure in patients with congestive heart failure.96 Garlic has been reported to reduce ischemia and reperfusion-induced arrhythmias. These effects could, at least in part, be the result of antioxidant activity, because it has been reported to be a powerful scavenger of oxygen free radicals.97,98 A garlic dialysate was reported to suppress premature ventricular contractions and ventricular tachycardia in

77

Chung

Cardiology in Review Volume 12, Number 2, March/April 2004

ouabain-toxic dogs and ectopic rhythm induced by isoprenaline and aconitine on paced rat left atria.99 In the atrium, effective refractory period and sinus node recovery time were prolonged. Ginkgo biloba (ginkgo, maidenhair tree, kew tree) extracts can have free-radical scavenging activity as well as antiarrhythmic effects. In one canine study of ischemia reperfusion, intravenous EGb 761, a Ginkgo biloba extract, reduced ventricular premature beat counts, duration of ventricular tachycardia, and reperfusion-associated ventricular brillation, although incidences of ischemic-induced ventricular tachycardia and brillation were similar.100 In a rat model, EGb 761 reduced ischemiareperfusion-indced ventricular arrhythmias in a dose-dependent manner.101 It has been suggested that these effects could be the result of the antioxidant properties of ginkgo biloba.102 EGb 761 may adjust the level of nitric oxide and inhibit oxygen freeradical-induced lipid peroxidation in myocardial ischemia reperfusion injury.101 Other herbs reportedly showing reduction in ischemia or reperfusion-induced arrhythmia models include ethanol extract of Sophora avescens;103 methanol extracts of Harpagophytum procumbens (devils claw) secondary roots and harpagoside,104 which also reduced arrhythmias induced by aconitine, calcium chloride, and epinephrine-chloroform; fumitory (Fumaria ofcinalis; earth smoke), which reduced ischemia-induced arrhythmias in dogs;105 Angelica;106 honokiol (in Magnolia ofcinalis);107,108 and bergenin (extract of Fluggea virosa).109

Other Herbs With Reported Antiarrhythmic or Electrophysiologic Activity

Ginseng forms appear to have potential for electrophysiological effects. In one study, Panax notoginseng (pseudoginseng) saponin Rg1 prolonged sinus node recovery time, atrioventricular Wenckebach conduction cycle length, ventricular effective refractory period, and ventricular action potential durations and increased ventricular brillation threshold in open-chest dogs.112 The authors suggested that the electrophysiological effects were similar to those of amiodarone. Panax notoginseng has been used for angina and hypertension; it also enhances synthesis of tissue-type plasminogen-activating factor, interferes with proliferation of smooth muscle cells, and dilates coronary arteries.76,113115 It has been reported to be a novel selective calcium ion antagonist that does not interact with L-type calcium channel but could interact with the receptor-operated calcium channel.116 Eleutherococcus (Eleutherococcus senticosus, Acanthopanax senticosus, Hedera senticosa; Devils shrub, Eleutherococcus, shigoka, Siberian ginseng, touch-me-not, wild pepper; ciwujia) is commonly called Siberian ginseng and belongs to the same family (Araliceae) as Panax ginseng. Ciwujia (Acanthopanax senticosus Harms), used for athletic performance and weight loss, could have antiarrhythmic effects. Ciwujia extract reduced reperfusion-induced ventricular brillation and ventricular tachycardia in the isolated rat heart.117 Ciwujia extract reduced the number of cells with abnormal action potential congurations, suggesting protection of the myocardium from ischemic-induced electrophysiological abnormalities. Siberian ginseng can cause an apparent increase in digoxin.78 Experimentally, licorice root has been reported to have antiarrhythmic effects.117 Zhigancao (prepared licorice) injection can antagonize arrhythmias induced by chloroform, adrenaline, aconitine, strophanthin K, and barium chloride. It may slow the heart rate, prolong P-R and Q-T intervals, and antagonize the positive chronotropic response induced by isoprenaline.118 Another component of licorice, sodium 18 beta-glycyrrhetate, strongly counteracts arrhythmia induced by chloroform, lengthens the appearance time of arrhythmia induced by CaCl2, slightly retards the heart rate of rats and rabbits, and partly antagonizes the acceleration effect of isoproterenol on rabbit hearts.119 However, licorice can also induce arrhythmias by inducing hypokalemia.120 Various alkaloids from plants have been reported to have antiarrhythmic activity. Alkaloids from plants of the Aconitum and Delphinium species, being studied for analgesic and antiinammatory effects, may have cardiac electrophysiological effects. Lappaconitine and its metabolite N-deacetyllappaconitine inhibit tetrodotoxin-sensitive, voltage-dependent sodium channels in atria.121 Cardiotoxicity, primarily of atrial asystole, was lower compared with aconi 2004 Lippincott Williams & Wilkins

Chinese Herbs Used to Suppress Palpitations

Several Chinese herbal preparations can have antiarrhythmic effects and have been used to suppress palpitations. Xin bao, ci zhu wan, bu xin dan, yu zhu (Rhizoma Polignati odorati), and mai dong (Radix Ohniopogonis, or qi lu tang containing glycyrrhizae [licorice] and Sophora avescens) are Chinese herbs that have been used to treat patients with palpitations. However, few clinical trials have been conducted to assess their effects and safety. In one study, 84 patients with symptomatic ventricular premature beats were treated with a herbal regimen containing Mai Dong with more than 80% of patients reporting symptom relief with no observed side effects.110 In one observational study of 87 patients with sick sinus syndrome, Xin bao administered orally 2 to 3 times per day for 2 months was reported to improve symptoms of sick sinus syndrome such as dizziness, palpitations, and chest pressure.111 The mechanism of action of Xin bao was thought to be through stimulation and increased excitability of the sinoatrial node. However, no randomized, controlled trials studying the efcacy of these herbs have been done to date.

78

Cardiology in Review Volume 12, Number 2, March/April 2004

Vitamins, Supplements, Herbal Medicines, and Arrhythmias

tine (see Risks of Herbal or Nutritional Supplements). Liriodenine, an aporphine alkaloid derived from Fissistigma glaucescens, inhibits the Na and Ito channel and prolongs action potential duration with the effect of suppression of ventricular arrhythmias induced by ischemiareperfusion.122 Rhodiola rosea extract has been reported to reduce adrenalin or calcium chloride-induced arrhythmias. This effect can be eliminated by injection of naloxone, suggesting that the antiarrhythmic effect is associated with activation of the opioid system.123 Chicory (Chicorium intybus L., Blue sailors succory, wild succory) has been roasted and used to add avoring to coffee and tea or used as a substitute for coffee.77 Chicory extracts reduced isolated toad heart rate similar to that after quinidine. Berberine (Hydrastis canadensis) can block potassium channels and stimulate Na-Ca exchange. However, clinical studies of any potential antiarrhythmic effects have been lacking.

RISKS OF HERBAL OR NUTRITIONAL SUPPLEMENTS

The potential risks of herbal supplements have been highlighted by reports of sudden deaths. Potential hazards have received attention in several reviews.124 126 Ephedrine and other ephedrine alkaloids have been associated with many reports of adverse cardiovascular events. Dietary supplements containing ephedra (ma huang, epitonin), promoted for weight reduction, performance and energy enhancement, body building, and fat burning, contain catecholamines that can cause arrhythmias and even death.77,124,127,128 Many of these supplements also contain caffeine, which can potentiate the risk. Hypertension, palpitations, tachycardia, cardiac arrest or sudden death, myocardial infarction, stroke, and seizures have been reported to the Food and Drug Administration (FDA).127 Ventricular arrhythmias and hypertension have also been reported with herbal ecstasy, an herbal drug of abuse containing ephedrine and caffeine.129,130 Phenylpropanolamine is another ephedrine alkaloid associated with similar reports, particularly when it was marketed with caffeine. This combination was banned by the FDA. Other herbs with high levels of amines or sympathomimetic action include Agnus castus, black cohosh, cola, guarana (Paullinia cupana), mate , and St. Johns wort.77 Herbs containing sympathomimetic amines also include aniseed, capsicum, parsley, and vervain. Cola nut (Kola) contains caffeine. Herbs with sympathomimetic-blocking action include agrimony, celery, ginger, and hawthorn. Herbs containing anticholinergic agents include corkwood tree. Some supplements could potentially cause QT prolongation. A case of cardiac arrest resulting from torsades de pointes associated with a cesium supplement, being used for
2004 Lippincott Williams & Wilkins

cancer prevention has been reported.131 Cesium is a wellrecognized potassium channel blocker that is used in experimental animal models to induce prolongation of action potential duration, early afterdepolarizations, QT prolongation, and torsades de pointes. Grapefruit can increase the bioavailability of terfenadine (no longer available in the United States) and probably astemizole; increases in QT interval have been reported when grapefruit juice was used with terfenadine.77 Aconite (Aconitum napellus L., A. columbianum, Aconite, monkshood, friars cap, helmet ower, soldiers cap, wolfsbane) nds some use externally as antiinammatory and analgesic agents, but are highly toxic potentially even through percutaneous absorption.77 Aconitine and related alkaloids from aconite can be rapidly toxic and cause potentially fatal arrhythmias or death from paralysis of the respiratory center or cardiac muscle. Death has occurred in minutes to days. Bradycardia, panconduction defects manifested by sinus arrest, atrioventricular dissociation with idiojunctional rhythm, and left bundle branch block resulting in hypotension and syncope has been reported.132 Broom has been used as a cathartic, emetic, diuretic, decongestant, and antiarrhythmic agent, but is considered unsafe by the FDA.77 Sparteine, an alkaloid derivative, has been used to induce labor as an oxytocic agent and also as an antiarrhythmic agent. Broom can inhibit the transport of sodium ions across the cell membrane, but can cause tachyarrhythmias.77 Veratrum (hellebore), initially used for hypertension, contains alkaloids that can cause nausea, vomiting, bradycardia, atrioventricular dissociation, and hypotension, and rare seizures.76,133 Veratrum alkaloids act on left ventricle and coronary sinus baroreceptors, causing a Bezold-Jarisch vagal reex hypotension and bradycardia.133,134 The bradycardia usually responds to atropine. Potassium loss can be produced by ingestion of licorice, advocated for peptic ulcer disease or other gastrointestinal symptoms. Licorice can cause pseudoaldosteronism with hypertension and hypokalemia.78 Herbs with diuretic activity that could potentiate arrhythmias if hypokalemia occurs include corn silk, dandelion, juniper, and uva ursi.77 Thyroid dysfunction can be induced by some supplements. Horseradish (used as an antiseptic with circulatory and digestive stimulation effects and as a diuretic, for pulmonary and urinary tract infections, urinary stones, edema, and externally to inamed joints or tissues) can depress thyroid function. Kelp, used for weight loss, contains iodine and can cause hyperthyroidism; it has also caused myxedema in patients sensitive to iodide. Thyroid hormone has also been reported to be an adulterant in certain Chinese herbal dietary preparations.125

79

Chung

Cardiology in Review Volume 12, Number 2, March/April 2004

Interactions With Digoxin

As noted previously, multiple plants contain cardiac glycosides, which can produce digoxin-like effects, potentiation of digitalis action, and/or elevation of digoxin levels. Many of these contain digoxin immunocrossreactivity, elevating digoxin levels. Examples of herbs or supplements that may interact with digoxin or digoxin levels include ginseng, hawthorn, kyushin, licorice, plantain, squill (Urginea maritime), and usara root. Siberian ginseng may interact with the digoxin assay, causing an increase in digoxin levels.78 Hawthorn (Crataegus) reportedly potentiates digoxin activity, but animal studies report beta-blocking or angiotensin-converting enzyme inhibition activity.78 Kyushin, a Chinese medicine containing chan su (Bufo bufo gargarizans cantor toad venom), may crossreact with digoxin assays and/or have digoxin-like action.78 Plantain (ribwort, Plantago), an herbal laxative, was reported to be adulterated with woolly foxglove in one preparation, elevating digoxin levels and resulting in cases of digitalis toxicity.135 Uzara root can have digoxintype cardiac effects. St. Johns wort has been reported to decrease the bioavailability of digoxin.136 Toxic reactions and overdoses have been frequently reported with cardioactive glycoside-containing herbs and supplements, particularly with oleander (dogbane, laurier rose, rose bay, anvirzel) with which death has been reported in a case after ingestion of only one leaf.137 Acute yellow oleander (Thevetia peruviana) poisoning has manifested with high serum cardiac glycoside levels and conduction defects affecting the sinus and atrioventricular nodes.138,139 Deaths after drinking herbal oleander (Nerium oleander) leaf tea has been reported and associated with elevation in serum digoxin levels, arrhythmias, hyperkalemia, and inactivation of the Na-K ATPase pump.140,141 Cardioactive glycoside toxicity can manifest as ventricular arrhythmias, bradycardia, and atrioventricular block. Detection of digoxin levels in such patients without obvious use of digoxin should trigger inquiry as to herbal or other supplement use. Digoxin-specic Fab antibody fragments may be helpful in the treatment of intoxication with such agents.76

dong quai (Angelica sinensis), English camomile, fenugreek, feverfew (inhibits platelets through neutralization of sulfydryl groups, possible inhibition of eicosanoid generation), sh oil, gamma linolenic acid (in borage seed oil), garlic (decreased platelet aggregation), ginger (inhibitor of thromboxane synthetase, prolongs bleeding time), gingko leaf extract (ginkgolide B, a potent inhibitor of platelet-activating factor needed to induce arachidonate-independent platelet aggregation), goldenseal, guar gum, horse chestnut seed, kava (platelet inhibitor), licorice root, lovage root, meadowsweet, onion, panax ginseng, papain, parsley, passionower, poplar, quassia, red clover, rue, Siberian ginseng, sweet clover, St. Johns wort, turmeric, vitamins C and E, and willow bark. Cases have been reported of boldo-fenugreek, danshen (tan seng; root of Salvia miltiorrhiza), dong quai, devils claw, gingko biloba, papain, and vitamin E increasing the effect of warfarin with prolongation of PT/INRs.143,144 In addition, vitamin K constituents that may antagonize warfarin action have been reported in agrimony, plantain, stinging nettle, green tea, and vitamin K. Cases of Coenzyme Q10, ginseng, and green tea antagonizing the effect of warfarin have been reported. A reduction in PT/INR when these agents have been used in patients on previously stable doses of warfarin has been documented. St. Johns wort also induces CYP3A4 and intestinal P-glycoprotein, and can accelerate warfarin metabolism.145 Because of the potential for excessive bleeding risk or antagonism of warfarin action, it is usually recommended that concomitant use of most of these herbal supplements with warfarin should be avoided.

SUMMARY
With a large proportion of the general population potentially using nutritional and herbal supplements, it is critical to investigate the impact of such use in patients presenting with arrhythmias. Promising supplements that might be antiarrhythmic include omega-3 polyunsaturated acids, coenzyme Q10, and carnitine. Coenzyme Q10, used in treatment of heart failure, may reduce arrhythmias associated with myocardial infarction, heart failure, and reperfusion, potentially by prevention of fatty acid release from the mitochondria. Carnitine and its derivatives may prove to be effective in ischemia- or reperfusion-induced arrhythmias, potentially by reducing the accumulation of toxic long-chain fatty acids. Clinical data is strongest for omega-3 polyunsaturated fatty acids and sh oil supplementation which appear to reduce arrhythmias and reduce mortality and sudden death. Correction of electrolyte disturbances has been long advised, and magnesium supplementation has been benecial in the treatment of torsades de pointes and in some studies after cardiac surgery. However, routine electrolyte supplementation with empiric potassium or magnesium in nondecient patients has
2004 Lippincott Williams & Wilkins

Anticoagulant, Antiplatelet Effects, and Interactions With Warfarin

Multiple case reports have been published showing anticoagulant or antiplatelet effects of herbs or potential interactions of herbs with warfarin.78,142 Herbs possessing anticoagulant or antiplatelet activity or causing a potential increase in bleeding risk include acerola, angelica, anise, American ginseng, arnica, asafoetida, bilberry, bogbean, boldo, bromelain, capsicum, cayenne, celery, chamomile (coumarin activity), chlorella, clove (inhibitor of thromboxane synthetase), coenzyme Q, danshen (Salvia miltiorrhiza),

80

Cardiology in Review Volume 12, Number 2, March/April 2004

Vitamins, Supplements, Herbal Medicines, and Arrhythmias

not been convincingly benecial, and magnesium supplementation in acute myocardial infarction does not reduce mortality. Studies with vitamin E have been disappointing in that it does not appear to reduce mortality, although it could possibly impact sudden death. Several herbal supplements have also been promoted to have antiarrhythmic activity. However, clinical studies are lacking to support routine use of these herbal medications. In addition, some herbal supplements may cause serious proarrhythmia, and many supplements signicantly interact with warfarin and digoxin.

REFERENCES
1. Wahr JA, Parks R, Boisvert D, et al. Preoperative serum potassium levels and perioperative outcomes in cardiac surgery patients. Multicenter Study of Perioperative Ischemia Research Group. JAMA. 1999; 281:22032210. 2. Parra L, Fita G, Gomar C, et al. Plasma magnesium in patients submitted to cardiac surgery and its inuence on perioperative morbidity. J Cardiovasc Surg (Torino). 2001;42:37 42. 3. Oladapo OO, Falase AO. Congestive heart failure and ventricular arrhythmias in relation to serum magnesium. Afr J Med Med Sci. 2000;29:265268. 4. Maslow AD, Regan MM, Heindle S, et al. Postoperative atrial tachyarrhythmias in patients undergoing coronary artery bypass graft surgery without cardiopulmonary bypass: a role for intraoperative magnesium supplementation. J Cardiothorac Vasc Anesth. 2000;14:524 530. 5. Speziale G, Ruvolo G, Fattouch K, et al. Arrhythmia prophylaxis after coronary artery bypass grafting: regimens of magnesium sulfate administration. Thorac Cardiovasc Surg. 2000;48:2226. 6. Raghu C, Peddeswara Rao P, Seshagiri Rao D. Protective effect of intravenous magnesium in acute myocardial infarction following thrombolytic therapy. Int J Cardiol. 1999;71:209 215. 7. Gyamlani G, Parikh C, Kulkarni AG. Benets of magnesium in acute myocardial infarction: timing is crucial. Am Heart J. 2000;139:703. 8. Singh RB, Singh NK, Niaz MA, et al. Effect of treatment with magnesium and potassium on mortality and reinfarction rate of patients with suspected acute myocardial infarction. Int J Clin Pharmacol Ther. 1996;34:219 225. 9. Bhargava B, Chandra S, Agarwal VV, et al. Adjunctive magnesium infusion therapy in acute myocardial infarction. Int J Cardiol. 1995; 52:9599. 10. Shechter M, Hod H, Chouraqui P, et al. Magnesium therapy in acute myocardial infarction when patients are not candidates for thrombolytic therapy. Am J Cardiol. 1995;75:321323. 11. Ceremuzynski L, Gebalska J, Wolk R, et al. Hypomagnesemia in heart failure with ventricular arrhythmias. Benecial effects of magnesium supplementation. J Intern Med. 2000;247:78 86. 12. Parikka H, Toivonen L, Naukkarinen V, et al. Decreases by magnesium of QT dispersion and ventricular arrhythmias in patients with acute myocardial infarction. Eur Heart J. 1999;20:111120. 13. Bashir Y, Sneddon JF, Staunton HA, et al. Effects of long-term oral magnesium chloride replacement in congestive heart failure secondary to coronary artery disease. Am J Cardiol. 1993;72:1156 1162. 14. Steinberger HA, Hanson CW III. Outcome-based justication for implementing new point-of-care tests: there is no difference between magnesium replacement based on ionized magnesium and total magnesium as a predictor of development of arrhythmias in the postoperative cardiac surgical patient. Clin Lab Manage Rev. 1998;12:8790. 15. Ziegelstein RC, Hilbe JM, French WJ, et al. Magnesium use in the treatment of acute myocardial infarction in the United States (observations from the Second National Registry of Myocardial Infarction). Am J Cardiol. 2001;87:710. 16. Santoro GM, Antoniucci D, Bolognese L, et al. A randomized study of intravenous magnesium in acute myocardial infarction treated with direct coronary angioplasty. Am Heart J. 2000;140:891 897.

17. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet. 1995;345: 669 685. 18. Antman EM. Magnesium in acute myocardial infarction: overview of available evidence. Am Heart J. 1996;132:487 495; discussion 496 502. 19. Shechter M, Hod H, Chouraqui P, et al. Acute myocardial infarction without thrombolytic therapy: benecial effects of magnesium sulfate. Herz 1997;22(suppl 1):7376. 20. Seelig MS, Elin RJ, Antman EM. Magnesium in acute myocardial infarction: still an open question. Can J Cardiol. 1998;14:745749. 21. The Magnesium in Coronaries (MAGIC) Trial Investigators. Early administration of magnesium in acute myocardial infarction in the MAGIC Trial: a randomized controlled trial. Lancet. 2002;360:1189 1196. 22. Van Wagoner DR, Nerbonne JM. Molecular basis of electrical remodeling in atrial brillation. J Mol Cell Cardiol. 2000;32:11011117. 23. Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial brillation begets atrial brillation. A study in awake chronically instrumented goats. Circulation. 1995;92:1954 1968. 24. Mihm MJ, Yu F, Carnes CA, et al. Impaired myobrillar energetics and oxidative injury during human atrial brillation. Circulation. 2001;104: 174 180. 25. Carnes CA, Chung MK, Nakayama T, et al. Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial brillation. Circ Res. 2001;89:E32E38. 26. Pruthi S, Allison TG, Hensrud DD. Vitamin E supplementation in the prevention of coronary heart disease. Mayo Clin Proc. 2001;76:1131 1136. 27. Virtamo J, Rapola JM, Ripatti S, et al. Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Arch Intern Med. 1998;158:668 675. 28. Stephens NG, Parsons A, Schoeld PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347:781786. 29. Gruppo Italiano per lo Studio della Sopravvivenza nellInfarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999;354:447 455. 30. Yusuf S, Dagenais G, Pogue J, et al. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:154 160. 31. Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet. 2001;357:89 95. 32. Trankmann P, Thiele R, Winnefeld K, et al. [Effect of administration of selenium and vitamin E on heart failure and ventricular arrhythmias in patients with acute myocardial infarct. ] Med Klin. 1999;94(suppl 3):78 80. 33. Langsjoen PH, Langsjoen AM. Overview of the use of CoQ10 in cardiovascular disease. Biofactors. 1999;9:273284. 34. Takamura T, Sugiyama S, Ozawa T. The effects of ubidecarenone derivatives on the action of phospholipase. Arzneimittelforschung. 1987;37:153156. 35. Ajioka M, Nagai S, Ogawa K, et al. The role of phospholipase in the genesis of reperfusion arrhythmia. J Electrocardiol. 1986;19:165172. 36. Singh RB, Wander GS, Rastogi A, et al. Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovasc Drugs Ther. 1998;12:347353. 37. Baggio E, Gandini R, Plancher AC, et al. Italian multicenter study on the safety and efcacy of coenzyme Q10 as adjunctive therapy in heart failure. CoQ10 Drug Surveillance Investigators. Mol Aspects Med. 1994;15:S287S294. 38. Fujioka T, Sakamoto Y, Mimura G. Clinical study of cardiac arrhythmias using a 24-hour continuous electrocardiographic recorder (5th

2004 Lippincott Williams & Wilkins

81

Chung

Cardiology in Review Volume 12, Number 2, March/April 2004

39. 40. 41.

42. 43. 44.

45. 46.

47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61.

report)antiarrhythmic action of coenzyme Q10 in diabetics. Tohoku J Exp Med. 1983;141(suppl):453 463. Arsenian MA. Carnitine and its derivatives in cardiovascular disease. Prog Cardiovasc Dis. 1997;40:265286. Whitmer JT, Idell-Wenger JA, Rovetto MJ, et al. Control of fatty acid metabolism in ischemic and hypoxic hearts. J Biol Chem. 1978;253: 4305 4309. Lango R, Smolenski RT, Narkiewicz M, et al. Inuence of L-carnitine and its derivatives on myocardial metabolism and function in ischemic heart disease and during cardiopulmonary bypass. Cardiovasc Res. 2001;51:2129. Retter AS. Carnitine and its role in cardiovascular disease. Heart Dis. 1999;1:108 113. Duan J, Moffat MP. Protective effects of D, L-carnitine against arrhythmias induced by lysophosphatidylcholine or reperfusion. Eur J Pharmacol. 1991;192:355363. Barbieri M, Carbonin PU, Cerbai E, et al. Lack of correlation between the antiarrhythmic effect of L- propionylcarnitine on reoxygenationinduced arrhythmias and its electrophysiological properties. Br J Pharmacol. 1991;102:7378. Carbonin PU, Ramacci MT, Pahor M, et al. Antiarrhythmic effect of L-propionylcarnitine in isolated cardiac preparations. Cardioscience. 1991;2:109 114. Broderick TL, Quinney HA, Barker CC, et al. Benecial effect of carnitine on mechanical recovery of rat hearts reperfused after a transient period of global ischemia is accompanied by a stimulation of glucose oxidation. Circulation. 1993;87:972981. Cacciatore L, Cerio R, Ciarimboli M, et al. The therapeutic effect of L-carnitine in patients with exercise-induced stable angina: a controlled study. Drugs Exp Clin Res. 1991;17:225235. Rizzon P, Biasco G, Di Biase M, et al. High doses of L-carnitine in acute myocardial infarction: metabolic and antiarrhythmic effects. Eur Heart J. 1989;10:502508. Di Biase M, Tritto M, Pitzalis MV, et al. Electrophysiologic evaluation of intravenous L-propionylcarnitine in man. Int J Cardiol. 1991;30: 329 333. Suzuki Y, Narita M, Yamazaki N. Effects of L-carnitine on arrhythmias during hemodialysis. Jpn Heart J. 1982;23:349 359. DiPalma JR, Ritchie DM, McMichael RF. Cardiovascular and antiarrhythmic effects of carnitine. Arch Int Pharmacodyn Ther. 1975;217: 246 250. Digiesi V, Cantini F, Bisi G, et al. L-carnitine adjuvant therapy in essential hypertension. Clin Ter. 1994;144:391395. Bonnet D, Martin D, Pascale De L, et al. Arrhythmias and conduction defects as presenting symptoms of fatty acid oxidation disorders in children. Circulation. 1999;100:2248 2253. Leaf A. Plasma nonesteried fatty acid concentration as a risk factor for sudden cardiac death: the Paris Prospective Study. Circulation. 2001; 104:744 745. Li Y, Kang JX, Leaf A. Differential effects of various eicosanoids on the production or prevention of arrhythmias in cultured neonatal rat cardiac myocytes. Prostaglandins. 1997;54:511530. Murnaghan MF. Effect of fatty acids on the ventricular arrhythmia threshold in the isolated heart of the rabbit. Br J Pharmacol. 1981;73: 909 915. McLennan PL, Abeywardena MY, Charnock JS. Dietary sh oil prevents ventricular brillation following coronary artery occlusion and reperfusion. Am Heart J. 1988;116:709 717. McLennan PL, Bridle TM, Abeywardena MY, et al. Dietary lipid modulation of ventricular brillation threshold in the marmoset monkey. Am Heart J. 1992;123:15551561. Billman GE, Kang JX, Leaf A. Prevention of ischemia-induced cardiac sudden death by n-3 polyunsaturated fatty acids in dogs. Lipids. 1997;32:11611168. Billman GE, Kang JX, Leaf A. Prevention of sudden cardiac death by dietary pure omega-3 polyunsaturated fatty acids in dogs. Circulation. 1999;99:24522457. Xiao YF, Kang JX, Morgan JP, et al. Blocking effects of polyunsaturated fatty acids on Na channels of neonatal rat ventricular myocytes. Proc Natl Acad Sci U S A. 1995;92:11000 11004.

62. Billman GE, Hallaq H, Leaf A. Prevention of ischemia-induced ventricular brillation by omega 3 fatty acids. Proc Natl Acad Sci U S A. 1994;91:4427 4430. 63. Kang JX, Xiao YF, Leaf A. Free, long-chain, polyunsaturated fatty acids reduce membrane electrical excitability in neonatal rat cardiac myocytes. Proc Natl Acad Sci U S A. 1995;92:3997 4001. 64. Kang JX, Leaf A. The cardiac antiarrhythmic effects of polyunsaturated fatty acid. Lipids. 1996;31(suppl):S41S44. 65. Kang JX, Leaf A. Evidence that free polyunsaturated fatty acids modify Na channels by directly binding to the channel proteins. Proc Natl Acad Sci U S A. 1996;93:35423546. 66. Leaf A. Omega-3 fatty acids and prevention of ventricular brillation. Prostaglandins Leukot Essent Fatty Acids. 1995;52:197198. 67. Sellmayer A, Witzgall H, Lorenz RL, et al. Effects of dietary sh oil on ventricular premature complexes. Am J Cardiol. 1995;76:974 977. 68. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, sh, and bre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989;2:757761. 69. Albert CM, Hennekens CH, ODonnell CJ, et al. Fish consumption and risk of sudden cardiac death. JAMA. 1998;279:2328. 70. Albert CM, Campos H, Stampfer MJ, et al. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med. 2002;346: 11131118. 71. de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alphalinolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. 1994;343:1454 1459. 72. Singh RB, Niaz MA, Sharma JP, et al. Randomized, double-blind, placebo-controlled trial of sh oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival-4. Cardiovasc Drugs Ther. 1997;11:485 491. 73. Siscovick DS, Raghunathan TE, King I, et al. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA. 1995;274:13631367. 74. Christensen JH, Gustenhoff P, Korup E, et al. Effect of sh oil on heart rate variability in survivors of myocardial infarction: a double blind randomised controlled trial. BMJ. 1996;312:677 678. 75. Christensen JH, Korup E, Aaroe J, et al. Fish consumption, n-3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction. Am J Cardiol. 1997;79: 1670 1673. 76. Mashour NH, Lin GI, Frishman WH. Herbal medicine for the treatment of cardiovascular disease: clinical considerations. Arch Intern Med. 1998;158:22252234. 77. The Review of Natural ProductsFacts and Comparisons; St. Louis: 2001. 78. Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug herb interactions. Arch Intern Med. 1998; 158:2200 2211. 79. Sutter MC, Wang YX. Recent cardiovascular drugs from Chinese medicinal plants. Cardiovasc Res. 1993;27:18911901. 80. Yu XC, Wu S, Wang GY, et al. Cardiac effects of the extract and active components of radix stephaniae tetrandrae. II. Myocardial infarct, arrhythmias, coronary arterial ow and heart rate in the isolated perfused rat heart. Life Sci. 2001;68:28632872. 81. Vanherweghem JL. [A new form of nephropathy secondary to the absorption of Chinese herbs]. Bull Mem Acad R Med Belg. 1994;149: 128 135. 82. Tekol Y, Gogusten B. Comparative determination of the cardioselectivity of taxine and verapamil in the isolated aorta, atrium and jejunum preparations of rabbits. Arzneimittelforschung. 1999;49:673 678. 83. Ozaki Y. [Pharmacological studies of indole alkaloids obtained from domestic plants, Uncaria rhynchophylla Miq. and Amsonia elliptica Roem et Schult]. Nippon Yakurigaku Zasshi. 1989;94:1726. 84. Masumiya H, Saitoh T, Tanaka Y, et al. Effects of hirsutine and dihydrocorynantheine on the action potentials of sino-atrial node, atrium and ventricle. Life Sci. 1999;65:23332341. 85. Kuramochi T, Chu J, Suga T. Gou-teng (from Uncaria rhynchophylla Miquel)-induced endothelium-dependent and -independent relaxations in the isolated rat aorta. Life Sci. 1994;54:20612069.

82

2004 Lippincott Williams & Wilkins

Cardiology in Review Volume 12, Number 2, March/April 2004

Vitamins, Supplements, Herbal Medicines, and Arrhythmias

86. Yano S, Horiuchi H, Horie S, et al. Ca2 channel blocking effects of hirsutine, an indole alkaloid from Uncaria genus, in the isolated rat aorta. Planta Med. 1991;57:403 405. 87. Wang XL, Zhang LM, Hua Z. Blocking effect of rhynchophylline on calcium channels in isolated rat ventricular myocytes. Zhongguo Yao Li Xue Bao. 1994;15:115118. 88. Vibes J, Lasserre B, Gleye J, et al. Inhibition of thromboxane A2 biosynthesis in vitro by the main components of Crataegus oxyacantha (Hawthorn) ower heads. Prostaglandins Leukot Essent Fatty Acids. 1994;50:173175. 89. Taskov M. On the coronary and cardiotonic action of crataemon. Acta Physiol Pharmacol Bulg. 1977;3:5357. 90. Garjani A, Nazemiyeh H, Maleki N, et al. Effects of extracts from owering tops of Crataegus meyeri A. Pojark on ischaemic arrhythmias in anaesthetized rats. Phytother Res. 2000;14:428 431. 91. al Makdessi S, Sweidan H, Dietz K, et al. Protective effect of Crataegus oxyacantha against reperfusion arrhythmias after global no-ow ischemia in the rat heart. Basic Res Cardiol. 1999;94:7177. 92. Rothfuss MA, Pascht U, Kissling G. Effect of long-term application of Crataegus oxyacantha on ischemia and reperfusion induced arrhythmias in rats. Arzneimittelforschung. 2001;51:24 28. 93. Popping S, Rose H, Ionescu I, et al. Effect of a hawthorn extract on contraction and energy turnover of isolated rat cardiomyocytes. Arzneimittelforschung. 1995;45:11571161. 94. Schussler M, Holzl J, Fricke U. Myocardial effects of avonoids from Crataegus species. Arzneimittelforschung. 1995;45:842 845. 95. Tauchert M, Gildor A, Lipinski J. [High-dose Crataegus extract WS 1442 in the treatment of NYHA stage II heart failure]. Herz. 1999;24: 465 474; discussion 475. 96. Holubarsch CJ, Colucci WS, Meinertz T, et al. Survival and prognosis: investigation of Crataegus extract WS 1442 in congestive heart failure (SPICE)rationale, study design and study protocol. Eur J Heart Fail. 2000;2:431 437. 97. Prasad K, Laxdal VA, Yu M, et al. Evaluation of hydroxyl radicalscavenging property of garlic. Mol Cell Biochem. 1996;154:55 63. 98. Rietz B, Belagyi J, Torok B, et al. The radical scavenging ability of garlic examined in various models. Boll Chim Farm. 1995;134:69 76. 99. Martin N, Bardisa L, Pantoja C, et al. Anti-arrhythmic prole of a garlic dialysate assayed in dogs and isolated atrial preparations. J Ethnopharmacol. 1994;43:1 8. 100. Lo HM, Lin FY, Tseng CD, et al. Effect of EGb 761, a ginkgo biloba extract, on early arrhythmia induced by coronary occlusion and reperfusion in dogs. J Formos Med Assoc. 1994;93:592597. 101. Shen J, Wang J, Zhao B, et al. Effects of EGb 761 on nitric oxide and oxygen free radicals, myocardial damage and arrhythmia in ischemiareperfusion injury in vivo. Biochim Biophys Acta. 1998;1406: 228 236. 102. Haramaki N, Aggarwal S, Kawabata T, et al. Effects of natural antioxidant ginkgo biloba extract (EGB 761) on myocardial ischemia reperfusion injury. Free Radic Biol Med. 1994;16:789 794. 103. Dai S, Chan MY, Lee SS, et al. The antiarrhythmic effects of Sophora avescens Ait in rats and mice. Am J Chin Med. 1986;14:119 123. 104. Zhang BF. [Effect of sophora alkaloids on experimental arrhythmia]. Zhong Yao Tong Bao. 1985;10:3738. 105. Gorbunov NP, Sukhanov AA, Bolotova MF. [Pharmacological correction of myocardial ischemia and arrhythmias in reversible coronary blood ow disorders and experimental myocardial infarct in dogs]. Kardiologiia. 1980;20:84 87. 106. Zhuang XX. [Protective effect of Angelica injection on arrhythmia during myocardial ischemia reperfusion in rat]. Zhong Xi Yi Jie He Za Zhi. 1991;11:360 361, 326. 107. Tsai SK, Huang SS, Hong CY. Myocardial protective effect of honokiol: an active component in Magnolia ofcinalis. Planta Med. 1996; 62:503506. 108. Hong CY, Huang SS, Tsai SK. Magnolol reduces infarct size and suppresses ventricular arrhythmia in rats subjected to coronary ligation. Clin Exp Pharmacol Physiol. 1996;23:660 664. 109. Pu HL, Huang X, Zhao JH, et al. Bergenin is the antiarrhythmic principle of Fluggea virosa. Planta Med. 2002;68:372374.

110. Wang X, Zhang J, Shi D, et al. Clinical observation on 84 cases of ventricular premature beat with deciency syndrome treated by qi lu tang. J Tradit Chin Med. 1998;18:83 86. 111. Chen ZY. [Use of xin bao in the treatment of 87 patients with sick sinus syndrome]. Zhong Xi Yi Jie He Za Zhi. 1990;10:529 531, 516. 112. Wu W, Zhang XM, Liu PM, et al. Effects of Panax notoginseng saponin Rg1 on cardiac electrophysiological properties and ventricular brillation threshold in dogs. Zhongguo Yao Li Xue Bao. 1995;16:459 463. 113. Zhang W, Wojta J, Binder BR. Effect of notoginsenoside R1 on the synthesis of tissue-type plasminogen activator and plasminogen activator inhibitor-1 in cultured human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol. 1994;14:1040 1046. 114. Lin SG, Zheng XL, Chen QY, et al. Effect of Panax notoginseng saponins on increased proliferation of cultured aortic smooth muscle cells stimulated by hypercholesterolemic serum. Zhongguo Yao Li Xue Bao. 1993;14:314 316. 115. Lei XL, Chiou GC. Cardiovascular pharmacology of Panax notoginseng (Burk) F. H. Chen and Salvia miltiorrhiza. Am J Chin Med. 1986;14:145152. 116. Kwan CY. Vascular effects of selected antihypertensive drugs derived from traditional medicinal herbs. Clin Exp Pharmacol Physiol. 1995; 22(suppl 1):S297S299. 117. Tian BJ, Gao TL, Song ZL. [Effects of ciwujia (Acanthopanax senticosus Harms) on reperfusion-induced arrhythmia and action potential alterations in the isolated rat heart]. Zhongguo Zhong Yao Za Zhi. 1989;14:493 495, 508, 512. 118. Chen R, Yuan C. [Experimental anti-arrhythmic effects of zhigancao (prepared licorice) injection]. Zhongguo Zhong Yao Za Zhi. 1991;16: 617 619, inside back cover. 119. Klepser TB, Klepser ME. Unsafe and potentially safe herbal therapies. Am J Health Syst Pharm. 1999;56:125138; quiz 139 141. 120. Bocker D, Breithardt G. [Induction of arrhythmia by licorice abuse]. Z Kardiol. 1991;80:389 391. 121. Heubach JF, Schule A. Cardiac effects of lappaconitine and N-deacetyllappaconitine, two diterpenoid alkaloids from plants of the Aconitum and Delphinium species. Planta Med. 1998;64:2226. 122. Chang GJ, Wu MH, Wu YC, et al. Electrophysiological mechanisms for antiarrhythmic efcacy and positive inotropy of liriodenine, a natural aporphine alkaloid from Fissistigma glaucescens. Br J Pharmacol. 1996;118:15711583. 123. Lishmanov Iu B, Maslova LV, Maslov LN, et al. [The anti-arrhythmia effect of Rhodiola rosea and its possible mechanism]. Biull Eksp Biol Med. 1993;116:175176. 124. De Smet PA. Herbal remedies. N Engl J Med. 2002;347:2046 2056. 125. Marcus DM, Grollman AP. Botanical medicinesthe need for new regulations. N Engl J Med. 2002;347:20732076. 126. Ernst E. Cardiovascular adverse effects of herbal medicines: a systematic review of the recent literature. Can J Cardiol. 2003;19:818 827. 127. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med. 2000;343:18331838. 128. Samenuk D, Link MS, Homoud MK, et al. Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine. Mayo Clin Proc. 2002;77:1216. 129. Zahn KA, Li RL, Purssell RA. Cardiovascular toxicity after ingestion of herbal ecstasy. J Emerg Med. 1999;17:289 291. 130. Yates KM, OConnor A, Horsley CA. Herbal ecstasy: a case series of adverse reactions. N Z Med J. 2000;113:315317. 131. Saliba W, Erdogan O, Niebauer M. Polymorphic ventricular tachycardia in a woman taking cesium chloride. Pacing Clin Electrophysiol. 2001;24:515517. 132. Guha S, Dawn B, Dutta G, et al. Bradycardia, reversible panconduction defect and syncope following self-medication with a homeopathic medicine. Cardiology. 1999;91:268 271. 133. Jaffe AM, Gephardt D, Courtemanche L. Poisoning due to ingestion of Veratrum viride (false hellebore). J Emerg Med. 1990;8:161167. 134. Quatrehomme G, Bertrand F, Chauvet C, et al. Intoxication from Veratrum album. Hum Exp Toxicol. 1993;12:111115.

2004 Lippincott Williams & Wilkins

83

Chung

Cardiology in Review Volume 12, Number 2, March/April 2004

135. Slifman NR, Obermeyer WR, Aloi BK, et al. Contamination of botanical dietary supplements by Digitalis lanata. N Engl J Med. 1998;339: 806 811. 136. Fugh-Berman A. Herb drug interactions. Lancet. 2000;355:134 138. 137. Szabuniewicz M, McCrady JD, Camp BJ. Treatment of experimentally induced oleander poisoning. Arch Int Pharmacodyn Ther. 1971;189: 1221. 138. Eddleston M, Ariaratnam CA, Sjostrom L, et al. Acute yellow oleander (Thevetia peruviana) poisoning: cardiac arrhythmias, electrolyte disturbances, and serum cardiac glycoside concentrations on presentation to hospital. Heart. 2000;83:301306. 139. de Nishioka SA, Resende ES. Transitory complete atrioventricular block associated to ingestion of Nerium oleander. Rev Assoc Med Bras. 1995;41:60 62.

140. Haynes BE, Bessen HA, Wightman WD. Oleander tea: herbal draught of death. Ann Emerg Med. 1985;14:350 353. 141. Osterloh J, Herold S, Pond S. Oleander interference in the digoxin radioimmunoassay in a fatal ingestion. JAMA. 1982;247:1596 1597. 142. Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm. 2000;57: 12211227; quiz 1228 1230. 143. Page RL II, Lawrence JD. Potentiation of warfarin by dong quai. Pharmacotherapy. 1999;19:870 876. 144. Lambert JP, Cormier A. Potential interaction between warfarin and boldo-fenugreek. Pharmacotherapy. 2001;21:509 512. 145. Moore LB, Goodwin B, Jones SA, et al. St. Johns wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci U S A. 2000;97:7500 7502.

84

2004 Lippincott Williams & Wilkins