Vitamins, Supplements, Herbal Medicines, And Arrhythmias

ORIGINAL ARTICLE

Vitamins, Supplements, Herbal Medicines, and Arrhythmias

Mina K. Chung, MD

Abstract: Nutritional and herbal supplements may have harmful orbeneficial effects on arrhythmias. Potential supplements that mayhave antiarrhythmic activity include omega-3 polyunsaturated fattyacids (N-3 PUFA), coenzyme Q10, and carnitine. Clinical studiesshow that N-3 PUFA or fish oil supplementation appears to reducemortality and sudden death. Coenzyme Q10, used in treatment ofheart failure, and carnitine and its derivatives may have beneficialeffects on arrhythmias, although clinical studies have been limited.Antioxidant supplements may be beneficial, but large studies withvitamin E have been disappointing in that it does not reducemortality. Correction of electrolyte disturbances has been longadvised and magnesium supplementation has been beneficial in thetreatment of torsades de pointes and in some studies after cardiacsurgery. However, routine electrolyte supplementation with empiricpotassium or magnesium in non-deficient patients has not beenconvincingly beneficial. Several herbal supplements have also beenpromoted to have antiarrhythmic activity. However, clinical studiesare lacking to support routine use of these herbal medications. Inaddition, some herbal supplements may cause serious proarrhyth-mia, and many supplements significantly interact with warfarin anddigoxin.

Key Words: arrhythmias, herbal medicine, vitamins, electrolytes,supplements

(Cardiology in Review 2004;12: 73–84)

Because vitamin and herbal supplement use has grownsignificantly in the general population, it is of increasing

importance to investigate and assess the potential impact ofthese supplements on cardiac arrhythmias. Some supplementscan have proarrhythmic effects either alone or in combinationwith conventionally prescribed medications. However, someagents might prove to be beneficial, and several of our moreeffective conventional antiarrhythmic agents have developedfrom herbal/plant sources.

ELECTROLYTES

PotassiumHypokalemia has been associated with increases in

arrhythmias, including atrial and ventricular ectopy, tachy-cardias, and prolonged QT-associated torsades de pointes. Astudy of perioperative hypokalemia reported that serum po-tassium levels �3.5 mmol/L increased perioperative arrhyth-mias after coronary artery bypass surgery.1 Hypokalemia is acommon sequela of diuretic use and can also occur in the userof licorice. Supplementation in potassium-deficient patientswith arrhythmias is advised to maintain a potassium concen-tration of �4.0 mmol/L. Whether potassium supplementationreduces arrhythmia or sudden death risk perioperatively orchronically in nondeficient patients has not been studied.

MagnesiumAs in hypokalemia, hypomagnesemia has been associ-

ated with increased arrhythmias, including postoperatively orin the setting of congestive heart failure.2,3 Loop and thia-zide-type diuretics can cause magnesium loss. The benefits ofmagnesium supplementation in the treatment of prolongedQT-induced torsades de pointes have been well established.In this condition, treatment often includes 1 to 2 g magnesiumsulfate given intravenously.

Magnesium has been reported to increase ventricularfibrillation threshold and prolong sinus node refractorinessand atrioventricular nodal conduction. However, althoughmany studies have reported that magnesium supplementationdecreased arrhythmias after cardiac surgery,4,5 myocardialinfarction,6–10 or congestive heart failure,11–13 other studieshave produced disappointing results.14–16 In ISIS-4,17 58,050patients with suspected acute myocardial infarction wererandomized to oral captopril versus placebo, oral mononitrateversus placebo, and 24 hours of intravenous magnesium (8mmol followed by 72 mmol) versus open control. Magne-sium failed to reduce mortality. Nevertheless, subsequentstudies have suggested that early rather than later intravenousmagnesium could be beneficial.18–20 A large randomized trialof early intravenous magnesium in acute myocardial infarc-tion in 6.213 patients showed no effect on 30 day mortality.21

In summary, acute intravenous magnesium has been anestablished treatment of treatment of torsades de pointes. Itcould have some benefits in reducing arrhythmias after car-

From the Department of Cardiovascular Medicine, The Cleveland ClinicFoundation, Cleveland, Ohio.

Reprints: Mina K. Chung, MD, Department of Cardiovascular Medicine, TheCleveland Clinic Foundation, 9500 Euclid Avenue, Desk F-15, Cleve-land, OH [email protected]

Copyright © 2004 by Lippincott Williams & WilkinsISSN: 1061-5377/04/1202-0073DOI: 10.1097/01.crd.0000091839.22076.f4

Cardiology in Review • Volume 12, Number 2, March/April 2004 73

diac surgery. However, intravenous magnesium has not beenshown to reduce mortality after acute myocardial infarctionremain under study.

VITAMINS

Vitamin CVitamin C, or ascorbate, is an antioxidant that may

have value in some situations in which oxidative stress mightbe arrhythmogenic. Atrial fibrillation is a common arrhyth-mia in which perpetuation of the arrhythmia could be pro-moted by electrophysiological and structural remodeling.22

Early changes during atrial fibrillation or rapid atrial pacingstimulation include a shortening of atrial refractory period(ERP).23 Such shortening of ERP predisposes the atria toreentrant arrhythmias, and longer durations of rapid atrialstimulation lead to greater susceptibility to perpetuation ofatrial fibrillation.23 Atrial tissue from patients with chronicatrial fibrillation also show evidence of increased oxidativestress and peroxynitrite formation.24,25

Ascorbate has been shown to potentially attenuate theelectrophysiological changes and oxidative stress inducedduring 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 antioxi-dant and peroxynitrite decomposition catalyst, attenuatedpacing-induced atrial ERP shortening, tissue ascorbate levelreduction, and the increase in peroxynitrite formation.

Vitamin C was used in a non-randomized pilot studyfor the prevention of postoperative atrial fibrillation. Atrialfibrillation is a common complication occurring after cardiacsurgery with an incidence of 20% to 50%. Surgery is a potentstimulator of oxidative and inflammatory stress. In 43 pa-tients given 2 g ascorbic acid the night before coronary arterybypass surgery, followed by 500 mg doses twice daily for up to5 days after surgery, the incidence of postoperative atrial fibril-lation appeared to be reduced.25 Patients treated with ascorbatehad a 16.3% incidence of atrial fibrillation, compared with34.9% in age- and gender-matched control patients not givenvitamin C. The proposed mechanism is postulated to relate to areduction in oxidative stress induced by cardiac surgery. Arandomized, controlled trial is ongoing. The effect of chronicvitamin C use for nonpostoperative arrhythmias has not beenestablished.

Vitamin EVitamin E is also an antioxidant that has been studied

for its potential ability to slow progression of atherosclero-sis.26 Despite promising animal and early observational stud-ies suggesting a protective effect for development of coronaryheart disease and death from coronary disease, large-scalestudies have reported disappointing results for vitamin E

supplementation.27–31 The GISSI-Prevenzione trial of 11324patients surviving recent (�3 months) myocardial infarctionwere assigned 1 g omega-3 polyunsaturated fatty acids daily,300 mg vitamin E (synthetic alpha-tocopherol) daily, both, orplacebo for 3.5 years. Treatment with omega-3 polyunsatu-rated fatty acids, but not vitamin E, significantly lowered therisk of the combined primary end point of overall death,nonfatal myocardial infarction, and stroke.29 However, vita-min E reduced cardiovascular death by 20% and sudden deathby 35%. The Heart Outcomes Prevention Evaluation (HOPE)study randomized 9541 patients with vascular disease ordiabetes plus one other coronary risk factor to receive 400 IUvitamin E per day, 10 mg ramipril 10 per day, both, orplacebo for a mean of 4.5 years.30 Vitamin E produced nosignificant differences in myocardial infarction, stroke, orcardiovascular disease death. The Primary Prevention Project(PPP) randomized 4495 patients with one or more coronaryrisk factors to 100 mg aspirin per day, 300 mg vitamin E perday, both, or placebo.

31

Vitamin E produced no reduction inend points. With regard to the effect of vitamin E on arrhyth-mias, a small trial of vitamin E and selenium on heart failureand ventricular arrhythmias in patients with myocardial in-farction showed no differences in ventricular arrhythmias asshown on long-term ECG.32

In summary, vitamin E does not appear to reduceoverall or cardiovascular mortality. Except for a possiblereduction in sudden death seen in the GISSI-Prevenzionetrial, no other significant data has been reported that indicatesa beneficial effect on arrhythmias from vitamin E.

SUPPLEMENTS WITH REPUTED BENEFITS INARRHYTHMIA SUPPRESSION

Coenzyme Q10Coenzyme Q10 (ubidecarenone, CoQ10, E-0216) has

been used in the treatment of heart failure, mitochondrialdisease, hypertension, angina, and arrhythmias.33 It is anantioxidant, free-radical scavenger, and membrane stabilizer.Coenzyme Q10 and its derivatives have been shown to reducereperfusion arrhythmias in animal models, apparently relatedto prevention of phospholipase release of free fatty acids fromphospholipids. In animal models, pretreatment with coen-zyme Q10 or its derivatives reduced the incidence of reper-fusion arrhythmias from 32% to none.34,35

Arrhythmia suppression effects from coenzyme Q10has been studied in some clinical trials in humans. In arandomized, double-blind, placebo-controlled trial in 144patients with acute myocardial infarction, coenzyme Q10 at120 mg per day for 28 days reduced angina, improved poorventricular 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 coenzymeQ10 in 2664 patients with NYHA class II and III heart

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failure, clinical symptoms improved after 3 months, includingarrhythmia in 63%.37 Coenzyme Q10 was also reported toreduce premature ventricular depolarizations on Holter mon-itoring in 22% (6 of 27) of patients with diabetes or hyper-tension but no clinical organic heart disease.38

CarnitineCarnitine has an important role in long-chain fatty acid

oxidation; it is a carrier in the transport of activated long-chain fatty acids into the mitochondria where beta oxidationoccurs.39 In hypoxia, beta-oxidation becomes the rate-limit-ing step in lipid oxidation.39,40 In ischemia, when fatty acidoxidation is limiting, long-chain fatty acids, which are toxicto cells, can accumulate. L-carnitine or propionyl L-carnitinemay improve lipid oxidation in early ischemia or reperfusionand thereby reduce the toxic accumulation of these fattyacids. Carnitine also is involved in metabolism of branchedchain amino acids, stabilization of cell membranes, andscavenging of free radicals.41

Carnitine and its derivatives may reduce ischemia-induced arrhythmias or arrhythmias from other conditions inwhich toxic long-chain acylcarnitines accumulate. L-carni-tine and propionyl-L-carnitine can decrease intracellular ac-cumulation of toxic metabolites during ischemia42 by im-proving fatty acid oxidation. This can lead to protection bycarnitine or its derivatives of ischemic myocardial lipid mem-branes and protein enzymes and a reduction in ischemic orreperfusion associated ventricular arrhythmias, includingventricular fibrillation, as demonstrated in animal models.43–45

Another potential mechanism leading to a reduction in ischemicarrhythmias 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 mightpredispose to ventricular arrhythmias.41,46 In humans, L-carni-tine has been associated with reduction in ventricular arrhythmiafrequency in patients with angina pectoris47 or acute myocardialinfarction.48 Thus, carnitine may prove to be a promising ther-apy for ischemia or reperfusion-induced arrhythmias.

Carnitine supplementation has also been studiedfor other arrhythmias. Only minimal electrophysiologicalchanges detected after 30 mg/kg L-propionylcarnitine weregiven over 3 minutes with only a 5% shortening of sinuscycle length reported.49 Carnitine has been reported to de-crease the incidence of supraventricular and ventricular ar-rhythmias during hemodialysis.50 In a cat model, thresholdsfor electrically induced atrial fibrillation were increased by100 mg/kg intravenous carnitine.51 Another study reported areduction in ventricular extrasystoles in hypertensive patientstreated with 2 g oral L-carnitine per day.52

Carnitine supplementation may also be beneficial insome genetic defects of fatty acid metabolism, particularly indefects of long-chain fatty acid transport across the innermitochondrial membrane or other defects in which inter-

mediary metabolites of fatty acids, such as long-chain acyl-carnitines, accumulate and are arrhythmogenic.53 Whethercarnitine supplementation will improve arrhythmias in thesesyndromes remains to be demonstrated.

Omega-3 Fatty Acids and Fish OilFish oil and omega-3 fatty acids (N-3 polyunsaturated

fatty acids [N-3 PUFA]) have been demonstrated to havebeneficial effects on coronary heart disease prevention, mor-tality, and ventricular arrhythmias. Although N-6 fatty acidsappear to be arrhythmogenic, N-3 series fatty acids appear tohave antiarrhythmic effects. The n-6 fatty acids, particularlylinoleic acid, can be elongated and desaturated to arachidonicacid, and then oxygenated through cyclooxygenase to 2-se-ries prostaglandins and thromboxane, which have beenshown to be arrhythmogenic, except for prostacyclin.54,55 Incontrast, none of the 3-series cyclooxygenase products ofeicosapentaenoic acid (EPA) were arrhythmogenic and, infact, n-3 fatty acids appeared protective.

Animal models have demonstrated the arrhythmogeniceffects of long-chain saturated fatty acids and the antiarrhyth-mic effects of N-3 PUFA.56 Tuna fish oil supplementationreduced ventricular fibrillation during coronary artery occlu-sion and reperfusion in rats.57 In marmosets fed diets supple-mented with PUFA-rich tuna fish oil (N-3 PUFA) or sunflowerseed oil (N-6 PUFA), ventricular fibrillation threshold afteracute myocardial ischemia, induced by coronary artery occlu-sion, was reduced with PUFA.58 Fish oil was associated with alow incidence of sustained fibrillation. In a canine model ofpostinfarction sudden cardiac death, ischemic-induced ventricu-lar fibrillation was prevented in up to 87% of dogs by n-3 PUFAand intravenous administration of the purified n-3 PUFA, doco-sahexaenoic acid (DHA), or EPA.59,60

This protective effect appears to be the result of amembrane-stabilizing effect with a reduction in membraneelectrical excitability by suppression of L-type Ca�� (ICa-L)and voltage-dependent Na� (INa) channel currents.61,62 N-3PUFA prolongs the inactivated state of INa and shifts cells tomore negative resting membrane potentials.63–65 These ef-fects would be protective in ischemic areas in which theresting membrane potential is partially depolarized and closerto threshold. N-3 PUFA effects on ICa-L may include adecrease in Ca�� fluxes, Ca�� overload, and triggered ar-rhythmias from afterdepolarizations.60,66

Several clinical studies have reported beneficial effectsof N-3 PUFA on mortality, sudden death, and arrhythmias. Ina prospective, randomized, double-blind, placebo-controlled16-week trial of fish (cod liver) oil versus placebo sunflowerseed oil in 79 patients with frequent premature ventricularcomplexes without overt structural heart disease, fish oilreduced PVCs by �70% in 44% of patients compared with15% in the placebo group.67 The Diet and Reinfarction Trial(DART) randomized 2033 men after myocardial infarction to

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receive advice on 1 of 3 diet strategies: 1) reduction in fatintake to 30% of total energy and increase in ratio of poly-unsaturated to saturated fat; 2) increase in fatty fish intake toat least 2 200- to 400-g portions of fatty fish weekly or 1.5-gfish oil capsules; or 3) increase in cereal fiber to 18 g daily.68

The fatty fish advice group had a 29% reduction in 2 yearall-cause mortality compared with those who did not receivethis advice. The GISSI-Prevenzione trial of 11,324 patientssurviving recent (�3 months) myocardial infarction wereassigned 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 suddendeath. The Physicians’ Health Study69 reported that dietaryfish and N-3 PUFA intakes were associated with a lower riskof sudden death among 20,551 U.S. male physicians com-pleting a baseline questionnaire regarding fish consumption.Dietary fish intake was associated with a reduced risk ofsudden death and total mortality. The threshold for the effectappeared to be at 1 fish meal per week. The multivariaterelative risk of sudden death was 0.48 (52% lower risk) inmales who consumed fish at least once per week comparedwith men who had fish less than monthly. A lower risk ofsudden death was also seen when analyzed by any intake ofn-3 PUFA. Blood levels of long-chain N-3 fatty acids, foundin fish oil, were inversely correlated with risk of sudden deathin apparently healthy men followed in the Physicians’ Healthstudy.70 In this case-control substudy, 94 men who hadsudden death as their first manifestation of cardiovasculardisease were compared with 184 men matched for age andsmoking status. The relative risk of sudden death was signif-icantly lower in subjects with levels in the third and fourthquartiles. Besides the large-scale studies noted here, otherclinical studies have also reported significant reductions insudden cardiac death from n-3 PUFA.70–73 Omega-3 PUFAalso increased heart rate variability in survivors of myocardialinfarction randomized to fish oil or olive oil.74,75 A primarybeneficial effect of fish consumption and N-3 PUFA intakemay be through a reduction in the risk of fatal arrhythmias.

These findings have motivated ongoing trials, includinga randomized, placebo-controlled trial of fish oil comparedwith placebo, to look at the incidence of recurrent ventriculararrhythmias/shocks in patients who have ICDs and are at riskfor sudden death.

HERBAL SUPPLEMENTSConventional antiarrhythmic drugs that were discov-

ered from herbs or plants include quinidine (a stereoisomer ofquinine from cinchona bark), lidocaine, amiodarone (fromKhellin, originally from the herb ammi visnaga), digoxin(foxglove), and atropine (atropa belladonna, or nightshade).

Cardioactive Digoxin-Like GlycosidesMany plant sources of natural cardioactive glycosides

with positive inotropic action have been identified.76 Digi-toxin (derived from Digitalis purpurea [foxglove] or Digitalislanata), and digoxin (derived from Digitalis lanata)76 havebeen used for treatment of congestive heart failure and fortheir sinus nodal and atrioventricular nodal-slowing effects.Digitalis has also been derived from Digitalis ambigua (yel-low foxglove), Digitalis ferriginea (rusty foxglove), Digitalisgrandiflora, Digitalis lanata (yellow foxglove), and Digitalislutea (straw foxglove). Common names include foxglove,purple foxglove, throatwort, fairy finger, fairy cap, lady’sthimble, scotch mercury, lion’s mouth, witch’s bells, deadman’s bells, and wolly foxglove.77

Herbs containing cardiac glycosides or digoxin-likesubstances include76,78 Adonis vernalis and Adonis micro-carpa (adonis, false hellebore, pheasant’s eye); Apocynumandrosaemifolium and Apocynum cannabinum (dogbane,milkweed, wild ipecac, black Indian hemp); Asclepias tu-berosa (pleurisy root), Asclepias curassavica (redheaded cot-ton bush), and Asclepias friticosa (balloon cotton); Calotropisprecera (king’s crown); Carissa spectabilis (wintersweet);Cerebra manghas (sea mango); Cheiranthus cheiri (Wall-flower); Convallaria majalis (lily of the valley, convallaria);Cryptostegia grandiflora (rubber vine); Cystisus scoparius(broom); Digitalis ambigua (yellow foxglove); Digitalis fer-riginea (rusty foxglove); Digitalis grandiflora; Digitalis lanata(yellow foxglove); Digitalis lutea (straw foxglove); Digitalispurpurea (purple foxglove); Eleutherococcus senticosus (Si-berian ginseng); Helleborus niger (black hellebore); Helle-borus veridus; Leonurus cardiaca (motherwort); Nerium ole-ander (oleander); Scilla maritima (white squill); Scrophularianodosa (figwort); Strophantus hispidus and kombe (strophan-thus); Thevetia peruviana (yellow oleander); Urginea mari-tima (squill); and Uzarae radix (uzara root). Besides plantsources, a digitalis-like steroid, marinabufagenin, has beenextracted from Bufo marinus (cane toad) venom76 and theChinese toad Bufo bufo gargarizans cantor venom, which iscontained in kyushin.78

Toxic reactions and overdoses have been frequentlyreported with these glycoside-containing herbs or supple-ments (see subsequently in this article). Because of theirnarrow therapeutic window, it is advisable to avoid use ofthese herbs and other nonstandard supplements for treatmentof congestive heart failure or arrhythmias and instead useindicated conventional standardized digoxin preparations.

Herbs With Calcium Channel AntagonismExtracts from the root of the Chinese herb Stephania

tetrandra have been used to treat hypertension and have calciumchannel-blocking activity similar to that of verapamil.76 RadixStephaniae Tetrandrae (RST) extracts inhibit Ca�� influxand reperfusion arrhythmias. Tetrandrine and fanchinoline



are 2 of the major components of the alkaloid extract. Tet-randrine blocks T and L calcium channels, inhibiting bindingof diltiazem and methoxyverapamil to calcium channel-bind-ing sites.79 RST extract and tetrandrine inhibited arrhythmiasassociated with myocardial infarction in animal studies, butwithout as much heart rate inhibition during ischemia as seenwith verapamil.80 Tetrandrine has also been reported to decreasealdosterone production and have antineoplastic, immunosup-pressive, and mutagenic effects.79 However, tetrandrine is one ofthe herbs potentially causing rapidly progressive renal failure(Chinese herb nephropathy), although many patients had beenon a combination of herbs and stephania tetrandra could havealso been misidentified.81 Nevertheless, it has also caused livernecrosis in dogs; the safe dosage in humans has not beenestablished.79

Taxine, derived from English yew leaves (Taxus bac-cata L), has calcium channel blockade activity. Similar toverapamil, negative inotropic and chronotropic effects werereported on isolated atrium preparations with higher selectiv-ity for the heart over vessel and intestine than verapamil.82

Uncaria rhynchophylla and amsonia elliptica containindole alkaloids, which have electrophysiological effects inthe heart with potency that could approximate that of ajma-line, an antiarrhythmic drug that is also an indole alkaloid.These herbs contain hirsutine, rhynchophylline, isorhyncho-phylline, and dihydrocorynantheine.83 These and beta-yohim-bine isolated from amsonia elliptica have shown potentialreduction in aconitine-induced arrhythmias in mice andouabain-induced arrhythmias in guinea pigs.83 Hirsutine anddihydrocorynantheine affect action potentials of the sinoatrialnode, the atria, and the ventricles, leading to negative chro-notropic and antiarrhythmic actions. In sinoatrial prepara-tions, these increase cycle length, decrease slope of phase 4depolarization, and decrease maximum rate of rise and pro-long action potential duration.84 In ventricular and atrialpreparations, they decreased maximum rate of rise and pro-longed action potential duration. Uncaria rhynchophylla hasbeen reported to inhibit calcium channels, inhibit nicotine-induced dopamine release,79 stimulate endothelium-derivedrelaxing factor and/or nitric oxide release,85 and inhibit plate-let aggregation.79 In the rat aorta, hirsutine appears to blockCa�� channel activity mainly through inhibition of the volt-age-dependent Ca�� influx.86 Rhynchophylline exhibits L-type Ca�� channel-blocking activity.87 Uncaria rhyncho-phylla has been used in Chinese traditional medicine to treathypertension.76 However, clinical data establishing its safetyand efficacy in humans is lacking.

Herbs With Activity Against IschemicArrhythmias and Free Radicals

Several herbs have been reported to be protectiveagainst ischemic and/or reperfusion-induced arrhythmias,particularly in animal models. Many of these have antioxi-

dant, free-radical scavenging activity. These herbs includeCrataegus species (hawthorn), gingko biloba, garlic, andangelica. However, few have been tested in clinical studies inhumans.

Crataegus species (Crataegus oxyacantha, Crataeguslaevigata, and Crataegus monogyna; hawthorn, English haw-thorn, haw, maybush, whitethorn) have been reported to havecardiovascular and antiarrhythmic effects. Crataegus leaves,flowers, and fruits contain active oligomeric procyanins,catechins, flavonoids, including hyperoside (vitexin, rham-nose) rutin, hyperoside and vitexin-rhamnoside, leucoantho-cyanidins, and crataeguslactone (mixture of ursolic, oleanic,and crataegolic acids).76,77Animal studies suggest Crataegusextracts produce cAMP-independent inotropic effects, vaso-dilation, and antioxidant and antiinflammatory effects. Theycan also inhibit formation of thromboxane A2.88 Crataegusoxycantha has been used as a cardiac tonic for angina,hypertension, arrhythmias, and congestive heart failure. Cra-taegus has positive inotropic and negative chronotropic ef-fects, increases coronary perfusion, and has mild hypotensiveeffects.76,89 Crataegus extracts have been reported to reduceischemia-induced ventricular arrhythmias.90,91 However, onestudy of long-term (8 weeks) Crataegus oxyacantha feedingin rats reported an aggravation of ischemia and reperfusion-induced arrhythmias that might have been the result of anincrease in intracellular calcium concentration.92 Hawthornextract has also been reported to prolong effective refractoryperiods and to have possible sympathomimetic-blockingactivity.93 Crataegus can enhance activity of concomitantdigoxin.76 A mechanism of action for the cardiac effects ofCrataegus could involve 3�,5�-cyclic adenosine monophos-phate phosphodiesterase inhibition.94

The antiarrhythmic capacity of Crataegus extract hasbeen studied in some human clinical trials. In a study of 1011patients with NYHA stage II heart failure, high-dose Cratae-gus extract WS 1442 (Crataegutt novo 450, 1 tablet twice perday) was tested in an observational study over 24 weeks.95 Atthe end of the monitoring period, improved ejection fraction,slower resting pulse, improved exercise tolerance test, fa-tigue, palpitations, and exercise dyspnea, and fewer patientswith arrhythmias and ventricular extrasystoles at maximumexercise level were reported. Crataegus extract WS 1442 (2450 mg per day) is being studied in a randomized, placebo-controlled, double-blind study (SPICE) of cardiac death,nonlethal myocardial infarction, and hospitalization resultingfrom progression of heart failure in patients with congestiveheart failure.96

Garlic has been reported to reduce ischemia and reper-fusion-induced arrhythmias. These effects could, at least inpart, be the result of antioxidant activity, because it has beenreported to be a powerful scavenger of oxygen free radi-cals.97,98 A garlic dialysate was reported to suppress prema-ture ventricular contractions and ventricular tachycardia in



ouabain-toxic dogs and ectopic rhythm induced by isopren-aline and aconitine on paced rat left atria.99 In the atrium,effective refractory period and sinus node recovery time wereprolonged.

Ginkgo biloba (ginkgo, maidenhair tree, kew tree)extracts can have free-radical scavenging activity as well asantiarrhythmic effects. In one canine study of ischemia–reperfusion, intravenous EGb 761, a Ginkgo biloba extract,reduced ventricular premature beat counts, duration of ven-tricular tachycardia, and reperfusion-associated ventricularfibrillation, although incidences of ischemic-induced ventric-ular tachycardia and fibrillation were similar.100 In a ratmodel, EGb 761 reduced ischemia–reperfusion-indced ven-tricular arrhythmias in a dose-dependent manner.101 It hasbeen suggested that these effects could be the result of theantioxidant properties of ginkgo biloba.102 EGb 761 mayadjust the level of nitric oxide and inhibit oxygen free-radical-induced lipid peroxidation in myocardial ischemia–reperfusion injury.101

Other herbs reportedly showing reduction in ischemiaor reperfusion-induced arrhythmia models include ethanolextract of Sophora flavescens;103 methanol extracts of Harp-agophytum procumbens (devil’s claw) secondary roots andharpagoside,104 which also reduced arrhythmias induced byaconitine, calcium chloride, and epinephrine-chloroform;fumitory (Fumaria officinalis; earth smoke), which reducedischemia-induced arrhythmias in dogs;105 Angelica;106 hono-kiol (in Magnolia officinalis);107,108 and bergenin (extract ofFluggea virosa).109

Chinese Herbs Used to Suppress PalpitationsSeveral Chinese herbal preparations can have antiar-

rhythmic effects and have been used to suppress palpitations.Xin bao, ci zhu wan, bu xin dan, yu zhu (Rhizoma Polignatiodorati), and mai dong (Radix Ohniopogonis, or qi lu tangcontaining glycyrrhizae [licorice] and Sophora flavescens)are Chinese herbs that have been used to treat patients withpalpitations. However, few clinical trials have been con-ducted to assess their effects and safety. In one study, 84patients with symptomatic ventricular premature beats weretreated with a herbal regimen containing Mai Dong with morethan 80% of patients reporting symptom relief with no ob-served side effects.110 In one observational study of 87patients with sick sinus syndrome, Xin bao administeredorally 2 to 3 times per day for 2 months was reported toimprove symptoms of sick sinus syndrome such as dizziness,palpitations, and chest pressure.111 The mechanism of actionof Xin bao was thought to be through stimulation and in-creased excitability of the sinoatrial node. However, no ran-domized, controlled trials studying the efficacy of these herbshave been done to date.

Other Herbs With Reported Antiarrhythmic orElectrophysiologic Activity

Ginseng forms appear to have potential for electrophys-iological effects. In one study, Panax notoginseng (pseudog-inseng) saponin Rg1 prolonged sinus node recovery time,atrioventricular Wenckebach conduction cycle length, ven-tricular effective refractory period, and ventricular actionpotential durations and increased ventricular fibrillationthreshold in open-chest dogs.112 The authors suggested thatthe electrophysiological effects were similar to those ofamiodarone. Panax notoginseng has been used for angina andhypertension; it also enhances synthesis of tissue-type plas-minogen-activating factor, interferes with proliferation ofsmooth muscle cells, and dilates coronary arteries.76,113–115 Ithas been reported to be a novel selective calcium ion antag-onist that does not interact with L-type calcium channel butcould interact with the receptor-operated calcium channel.116

Eleutherococcus (Eleutherococcus senticosus, Acan-thopanax senticosus, Hedera senticosa; Devil’s shrub, Eleu-therococcus, shigoka, Siberian ginseng, touch-me-not, wildpepper; ciwujia) is commonly called Siberian ginseng andbelongs to the same family (Araliceae) as Panax ginseng.Ciwujia (Acanthopanax senticosus Harms), used for athleticperformance and weight loss, could have antiarrhythmiceffects. Ciwujia extract reduced reperfusion-induced ventric-ular fibrillation and ventricular tachycardia in the isolated ratheart.117 Ciwujia extract reduced the number of cells withabnormal action potential configurations, suggesting protec-tion of the myocardium from ischemic-induced electrophys-iological abnormalities. Siberian ginseng can cause an appar-ent increase in digoxin.78

Experimentally, licorice root has been reported to haveantiarrhythmic effects.117 Zhigancao (prepared licorice) in-jection can antagonize arrhythmias induced by chloroform,adrenaline, aconitine, strophanthin K, and barium chloride. Itmay slow the heart rate, prolong P-R and Q-T intervals, andantagonize the positive chronotropic response induced byisoprenaline.118 Another component of licorice, sodium 18beta-glycyrrhetate, strongly counteracts arrhythmia inducedby chloroform, lengthens the appearance time of arrhythmiainduced by CaCl2, slightly retards the heart rate of rats andrabbits, and partly antagonizes the acceleration effect ofisoproterenol on rabbit hearts.119 However, licorice can alsoinduce arrhythmias by inducing hypokalemia.120

Various alkaloids from plants have been reported tohave antiarrhythmic activity. Alkaloids from plants of theAconitum and Delphinium species, being studied for analge-sic and antiinflammatory effects, may have cardiac electro-physiological effects. Lappaconitine and its metaboliteN-deacetyllappaconitine inhibit tetrodotoxin-sensitive, volt-age-dependent sodium channels in atria.121 Cardiotoxicity,primarily of atrial asystole, was lower compared with aconi-



tine (see “Risks of Herbal or Nutritional Supplements”).Liriodenine, an aporphine alkaloid derived from Fissistigmaglaucescens, inhibits the Na� and Ito channel and prolongsaction potential duration with the effect of suppression ofventricular arrhythmias induced by ischemia–reperfusion.122

Rhodiola rosea extract has been reported to reduceadrenalin or calcium chloride-induced arrhythmias. This ef-fect can be eliminated by injection of naloxone, suggestingthat the antiarrhythmic effect is associated with activation ofthe opioid system.123

Chicory (Chicorium intybus L., Blue sailor’s succory,wild succory) has been roasted and used to add flavoring tocoffee and tea or used as a substitute for coffee.77 Chicoryextracts reduced isolated toad heart rate similar to that afterquinidine. Berberine (Hydrastis canadensis) can block potas-sium channels and stimulate Na�-Ca�� exchange. However,clinical studies of any potential antiarrhythmic effects havebeen lacking.

RISKS OF HERBAL OR NUTRITIONALSUPPLEMENTS

The potential risks of herbal supplements have beenhighlighted by reports of sudden deaths. Potential hazardshave received attention in several reviews.124–126

Ephedrine and other ephedrine alkaloids have beenassociated with many reports of adverse cardiovascularevents. Dietary supplements containing ephedra (ma huang,epitonin), promoted for weight reduction, performance andenergy enhancement, body building, and fat burning, containcatecholamines that can cause arrhythmias and evendeath.77,124,127,128 Many of these supplements also containcaffeine, which can potentiate the risk. Hypertension, palpi-tations, tachycardia, cardiac arrest or sudden death, myocar-dial infarction, stroke, and seizures have been reported to theFood and Drug Administration (FDA).127 Ventricular ar-rhythmias and hypertension have also been reported withherbal ecstasy, an herbal drug of abuse containing ephedrineand caffeine.129,130 Phenylpropanolamine is another ephed-rine alkaloid associated with similar reports, particularlywhen it was marketed with caffeine. This combination wasbanned by the FDA.

Other herbs with high levels of amines or sympatho-mimetic action include Agnus castus, black cohosh, cola,guarana (Paullinia cupana), mate, and St. John’s wort.77

Herbs containing sympathomimetic amines also include ani-seed, capsicum, parsley, and vervain. Cola nut (Kola) con-tains caffeine. Herbs with sympathomimetic-blocking actioninclude agrimony, celery, ginger, and hawthorn. Herbs con-taining anticholinergic agents include corkwood tree.

Some supplements could potentially cause QT prolon-gation. A case of cardiac arrest resulting from torsades depointes associated with a cesium supplement, being used for

cancer prevention has been reported.131 Cesium is a well-recognized potassium channel blocker that is used in exper-imental animal models to induce prolongation of actionpotential duration, early afterdepolarizations, QT prolonga-tion, and torsades de pointes. Grapefruit can increase thebioavailability of terfenadine (no longer available in theUnited States) and probably astemizole; increases in QTinterval have been reported when grapefruit juice was usedwith terfenadine.77

Aconite (Aconitum napellus L., A. columbianum, Ac-onite, monkshood, friar’s cap, helmet flower, soldier’s cap,wolfsbane) finds some use externally as antiinflammatory andanalgesic agents, but are highly toxic potentially eventhrough percutaneous absorption.77 Aconitine and relatedalkaloids from aconite can be rapidly toxic and cause poten-tially fatal arrhythmias or death from paralysis of the respi-ratory center or cardiac muscle. Death has occurred in min-utes to days. Bradycardia, panconduction defects manifestedby sinus arrest, atrioventricular dissociation with idiojunc-tional rhythm, and left bundle branch block resulting inhypotension and syncope has been reported.132

Broom has been used as a cathartic, emetic, diuretic,decongestant, and antiarrhythmic agent, but is consideredunsafe by the FDA.77 Sparteine, an alkaloid derivative, hasbeen used to induce labor as an oxytocic agent and also as anantiarrhythmic agent. Broom can inhibit the transport ofsodium ions across the cell membrane, but can cause tachy-arrhythmias.77

Veratrum (hellebore), initially used for hypertension,contains alkaloids that can cause nausea, vomiting, bradycar-dia, atrioventricular dissociation, and hypotension, and rareseizures.76,133 Veratrum alkaloids act on left ventricle andcoronary sinus baroreceptors, causing a Bezold-Jarisch vagalreflex hypotension and bradycardia.133,134 The bradycardiausually responds to atropine.

Potassium loss can be produced by ingestion of lico-rice, advocated for peptic ulcer disease or other gastrointes-tinal symptoms. Licorice can cause pseudoaldosteronismwith hypertension and hypokalemia.78 Herbs with diureticactivity that could potentiate arrhythmias if hypokalemiaoccurs include corn silk, dandelion, juniper, and uva ursi.77

Thyroid dysfunction can be induced by some supple-ments. Horseradish (used as an antiseptic with circulatory anddigestive stimulation effects and as a diuretic, for pulmonaryand urinary tract infections, urinary stones, edema, and ex-ternally to inflamed joints or tissues) can depress thyroidfunction. Kelp, used for weight loss, contains iodine and cancause hyperthyroidism; it has also caused myxedema inpatients sensitive to iodide. Thyroid hormone has also beenreported to be an adulterant in certain Chinese herbal dietarypreparations.125



Interactions With DigoxinAs noted previously, multiple plants contain cardiac

glycosides, which can produce digoxin-like effects, potenti-ation of digitalis action, and/or elevation of digoxin levels.Many of these contain digoxin immunocrossreactivity, ele-vating digoxin levels.

Examples of herbs or supplements that may interactwith digoxin or digoxin levels include ginseng, hawthorn,kyushin, licorice, plantain, squill (Urginea maritime), andusara root. Siberian ginseng may interact with the digoxinassay, causing an increase in digoxin levels.78 Hawthorn(Crataegus) reportedly potentiates digoxin activity, but ani-mal studies report beta-blocking or angiotensin-convertingenzyme inhibition activity.78 Kyushin, a Chinese medicinecontaining chan su (Bufo bufo gargarizans cantor toadvenom), may crossreact with digoxin assays and/or havedigoxin-like action.78 Plantain (ribwort, Plantago), an herballaxative, was reported to be adulterated with woolly foxglovein one preparation, elevating digoxin levels and resulting incases of digitalis toxicity.135 Uzara root can have digoxin-type cardiac effects. St. John’s wort has been reported todecrease the bioavailability of digoxin.136

Toxic reactions and overdoses have been frequentlyreported with cardioactive glycoside-containing herbs andsupplements, particularly with oleander (dogbane, laurierrose, rose bay, anvirzel) with which death has been reportedin a case after ingestion of only one leaf.137 Acute yellowoleander (Thevetia peruviana) poisoning has manifested withhigh serum cardiac glycoside levels and conduction defectsaffecting the sinus and atrioventricular nodes.138,139 Deathsafter drinking herbal oleander (Nerium oleander) leaf tea hasbeen reported and associated with elevation in serum digoxinlevels, arrhythmias, hyperkalemia, and inactivation of theNa-K ATPase pump.140,141

Cardioactive glycoside toxicity can manifest as ventric-ular arrhythmias, bradycardia, and atrioventricular block.Detection of digoxin levels in such patients without obvioususe of digoxin should trigger inquiry as to herbal or othersupplement use. Digoxin-specific Fab antibody fragmentsmay be helpful in the treatment of intoxication with suchagents.76

Anticoagulant, Antiplatelet Effects, andInteractions With Warfarin

Multiple case reports have been published showinganticoagulant or antiplatelet effects of herbs or potentialinteractions of herbs with warfarin.78,142 Herbs possessinganticoagulant or antiplatelet activity or causing a potentialincrease 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 thrombox-ane synthetase), coenzyme Q, danshen (Salvia miltiorrhiza),

dong quai (Angelica sinensis), English camomile, fenugreek,feverfew (inhibits platelets through neutralization of sulfydrylgroups, possible inhibition of eicosanoid generation), fish oil,gamma linolenic acid (in borage seed oil), garlic (decreasedplatelet aggregation), ginger (inhibitor of thromboxane syn-thetase, prolongs bleeding time), gingko leaf extract (ginkgol-ide B, a potent inhibitor of platelet-activating factor needed toinduce arachidonate-independent platelet aggregation), gold-enseal, guar gum, horse chestnut seed, kava (platelet inhibi-tor), licorice root, lovage root, meadowsweet, onion, panaxginseng, papain, parsley, passionflower, poplar, quassia, redclover, rue, Siberian ginseng, sweet clover, St. John’s wort,turmeric, vitamins C and E, and willow bark. Cases havebeen reported of boldo-fenugreek, danshen (tan seng; root ofSalvia miltiorrhiza), dong quai, devil’s claw, gingko biloba,papain, and vitamin E increasing the effect of warfarin withprolongation of PT/INRs.143,144

In addition, vitamin K constituents that may antagonizewarfarin action have been reported in agrimony, plantain,stinging nettle, green tea, and vitamin K. Cases of CoenzymeQ10, ginseng, and green tea antagonizing the effect of war-farin have been reported. A reduction in PT/INR when theseagents have been used in patients on previously stable dosesof warfarin has been documented. St. John’s wort also in-duces CYP3A4 and intestinal P-glycoprotein, and can accel-erate warfarin metabolism.145

Because of the potential for excessive bleeding risk orantagonism of warfarin action, it is usually recommended thatconcomitant use of most of these herbal supplements withwarfarin should be avoided.

SUMMARYWith a large proportion of the general population po-

tentially using nutritional and herbal supplements, it is criticalto investigate the impact of such use in patients presentingwith arrhythmias. Promising supplements that might be anti-arrhythmic include omega-3 polyunsaturated acids, coen-zyme Q10, and carnitine. Coenzyme Q10, used in treatmentof heart failure, may reduce arrhythmias associated withmyocardial infarction, heart failure, and reperfusion, poten-tially by prevention of fatty acid release from the mitochon-dria. Carnitine and its derivatives may prove to be effective inischemia- or reperfusion-induced arrhythmias, potentially byreducing the accumulation of toxic long-chain fatty acids.Clinical data is strongest for omega-3 polyunsaturated fattyacids and fish oil supplementation which appear to reducearrhythmias and reduce mortality and sudden death. Correc-tion of electrolyte disturbances has been long advised, andmagnesium supplementation has been beneficial in the treat-ment of torsades de pointes and in some studies after cardiacsurgery. However, routine electrolyte supplementation withempiric potassium or magnesium in nondeficient patients has



not been convincingly beneficial, and magnesium supplemen-tation in acute myocardial infarction does not reduce mortal-ity. Studies with vitamin E have been disappointing in that itdoes not appear to reduce mortality, although it could possi-bly impact sudden death. Several herbal supplements havealso been promoted to have antiarrhythmic activity. However,clinical studies are lacking to support routine use of theseherbal medications. In addition, some herbal supplementsmay cause serious proarrhythmia, and many supplementssignificantly interact with warfarin and digoxin.

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Vitamins, Supplements, Herbal Medicines, And Arrhythmias

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