Accepted Manuscript

Review of Complementary and Alternative Medical Treatment of Arrhythmias

Andrew Brenyo, MD Mehmet K. Aktas, MD

PII: S0002-9149(13)02389-8
DOI: 10.1016/j.amjcard.2013.11.044
Reference: AJC 20151

To appear in: The American Journal of Cardiology

Received Date: 5 October 2013

Revised Date: 12 November 2013
Accepted Date: 18 November 2013

Please cite this article as: Brenyo A, Aktas MK, Review of Complementary and Alternative
Medical Treatment of Arrhythmias, The American Journal of Cardiology (2014), doi: 10.1016/
j.amjcard.2013.11.044.

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 ACCEPTED MANUSCRIPT

Review of Complementary and Alternative Medical Treatment of

Arrhythmias

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Andrew Brenyo MD, Mehmet K. Aktas MD.

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Affiliations:

AJB: Greenville University Health System, Greenville South Carolina

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MKA: University of Rochester Medical Center, Rochester, New York

Grant/Financial Support: None

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Address for Correspondence

Andrew J Brenyo, MD
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Greenville University Health System

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Department of Medicine

701 Grove Road

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Greenville, South Carolina 29605

United States of America

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Telephone: (919) 724-7489

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Email: Andrew_Brenyo@urmc.rochester.edu

Running Title

Complementary and Alternative Treatment of Arrhythmias

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ABSTRACT

Complementary and alternative medical (CAM) therapies are commonly utilized by patients for

the treatment of medical conditions spanning the full spectrum of severity and chronicity. The

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use of alternative remedies both herbal and others for conditions lacking effective medical

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treatment is on the rise. Included within this categorization, arrhythmic disease absent effective

catheter based therapy or with medical therapy limited by the toxicities of contemporary

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antiarrhythmic agents is frequently managed by patients with CAM therapies without their

practitioner’s knowledge and in the face of potential herb / drug toxicities. This article reviews

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nine CAM therapies: seven individual herbal therapies along with acupuncture and yoga that
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have been studied and reported as having an antiarrhythmic effect. The primary focuses being

the proposed antiarrhythmic mechanism of each CAM along with interactions between the CAM
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therapy and commonly prescribed medical therapy for arrhythmia patients. We stress persistent
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vigilance on the part of the provider in discussing the use of herbal or other CAM’s within the
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arrhythmia population.
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Key Words: Complimentary and Alternative Medicine, Antiarrhythmic agents

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Contemporary medical literature is sparse regarding the safety and efficacy of commonly utilized

non-traditional arrhythmia therapies. In contrast, a cursory internet search reveals an astounding

number of websites discussing an impressive array of available alternative therapies for

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arrhythmias. Many of these complementary and alternative medical (CAM) remedies have

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antiarrhythmic properties similar to prescription antiarrhythmic agents and if taken

inappropriately, particularly in combination with prescription antiarrhythmic agents, may prove

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harmful. Moreover, many CAM therapies can alter the metabolism of other evidence based heart

failure or antiarrhythmic agents resulting in avoidable toxicity and adverse clinical events. This

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article reviews the efficacy and safety of CAM therapies (herbal, Yoga and acupuncture)
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reported as having antiarrhythmic activity or efficacy in PubMed. Our focus is CAM therapies

with known and described antiarrhythmic properties followed by the safety and drug-drug
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interactions of commonly utilized agents. The agents discussed are far from all inclusive and
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only those identified through the available medical literature are included.
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CAM’s with Reported Antiarrhythmic Properties

A list of the discussed CAM agents, their proposed mechanisms and known CAM / drug
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interactions is presented in Table 1.

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Motherwort (Leonurus Cardiaca)

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Motherwort (Leonurus Cardiaca) has a long history of use in both European and Asian

traditional medicine dating back to the 15th century secondary to its sedative and antispasmodic

properties. Used by the Greeks for the treatment of anxiety in pregnancy it acquired its name

Motherwort or “Mothers Herb”. Regarding cardiovascular maladies it has been used for a

generic “cardiac debility” and tachycardia or palpitations. Phenylpropanoid glycosides have

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been detected in multiple preparations of Motherwort and appear to play a dominant role in their

purported pharmacologic activity.1 In particular, lavandulifolioside a phenylpropanoid isolated

from Motherwort has been shown to have significant negative chronotropic effects and has been

shown to prolong the PR, QRS and QT intervals in rats.1

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Further work in isolated rabbit, rat and guinea pig hearts identified the electrophysiologic

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and related therapeutic effects of Motherwort.2 Prolongation of the activation time constant of If ,

antagonism of ICa.L, and reductions in the repolarizing current IK.r were observed with

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Motherwort preparations both at whole organ and single cell level.2 Such effects at the cellular

level explain the reduction in sinus rate (If) along with prolongation of the PQ interval (ICa.L,

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IK.r) seen at the organ level. Its antiarrhythmic activity is similar to class III antiarrhythmic
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agents with little effect on phase 0 of the action potential, prolongation of phase 2 and a

reduction in If resulting in a slowing of the sinus rate.

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Currently no data regarding the efficacy and safety of Motherwort for the treatment of
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palpitations or as an antiarrhythmic is available. In similar fashion, little is known about the

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metabolism of the pharmacologically active components of Motherwort. Given its antiplatelet

effects3, its use should be avoided in any patient on concurrent antiplatelet or anticoagulant
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therapy and/or those with a bleeding diathesis. As its effects on the cytochrome system remain

unknown, it should be used with caution in the setting of drugs whose metabolism is cytochrome
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dependent with narrow therapeutic windows.

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Wenxin Keli

Wenxin Keli is a Chinese herb extract reported to be of benefit in the treatment of cardiac

arrhythmias, cardiac inflammation, and heart failure.4 Wenxin Keli is composed of 5 agents:

Nardostachys chinensis Batal extract, Codonopsis, Notoginseng, amber, and Rhizoma

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Polygonati. In China it possesses a licensable indication for premature ventricular contractions

(PVC’s) which was included in the 2009 revision of the National Reimbursement Drug List.

Recent animal model work by Burashnikov et al. has supported the ability of Wenxin

Keli to suppress and prevent atrial fibrillation in dog models.4 Within this study the

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antiarrhythmic activity of Wenxin Keli occurred through a unique semi selective depression of

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atrial INa channels and prolongation of the atrial effective refractory period.4 The clinical

efficacy, metabolism and potential herb / drug interactions in human remains to be studied

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although its atrial selectivity makes it a very interesting potential pharmaceutical antiarrhythmic

agent.

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Cinchona (Cinchona, various species)
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Cinchona bark contains a number of quinone alkaloids, primarily quinine, quinidine,
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cinchonine, and cinchonidine. Quinine and its stereoisomer quinidine are the most familiar and

pharmacologically active of these compounds occurring in amounts of 0% to 14% by weight in

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cinchona bark.5 The use of cinchona bark for the treatment of malarial infections dates back to
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the 17th century. Its use as an antiarrhythmic was introduced in 1918 by Walter Frey as the

“common alkaloid” of cinchona bark and is still used as the purified class 1A antiarrhythmic
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quinidine today.

Given that it is the original source of quinidine, any antiarrhythmic effect and possible
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therapeutic benefit for the treatment of palpitations would be expected to result from the class 1A
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antiarrhythmic activity (prolongation of phase 0 and the entire action potential) of the quinidine.

No data regarding the antiarrhythmic benefit of cinchona is currently available. It is also

unknown if cinchona would have the same proarrhythmic effect and increased mortality seen

with other class 1 antiarrhythmics when used in patients with prior myocardial infarction.6

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The only significant medication interaction noted with cinchona is a decrease in systemic

levels of carbamazepine through induction of CYP3A4 via which it is metabolized.7 However,

such a short list may be secondary to a well described underreporting of adverse drug

interactions with CAM agents.8 With the active ingredients quinine and quinidine having a much

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better understood and extensive list of medication interactions, the cautious approach would be

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to assess for any possible interactions with these two agents.

Hawthorne (Crataegus oxycantha)

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Extract from the berries and flowers of the common Hawthorn plant (Crataegus

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oxycantha) is a popular herbal supplement widely used by herbalists for treatment of angina,

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arrhythmia, hypertension and congestive heart failure. Its use as a cardiovascular agent in

European medicine dates to first century Greek herbalist Dioscorides and later Swiss physician
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Paracelsus (1493–1541).9 As a contemporary CAM treatment for cardiovascular maladies it

remains in widespread use today.10

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Hawthorn has positive inotropic 11 and vasodilatory effects 12 and in related fashion is
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thought to increase myocardial perfusion and reduce afterload. Regarding antiarrhythmic effects,

Hawthorne extract has been shown to prolong the action potential through an inhibition of the
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inward potassium channels IKs and IKr 13. This effect is similar to that of class III antiarrhythmic

agents and forms the basis of the antiarrhythmic effects described for Hawthorn extract.13 Of
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note, Hawthorn appears to be selectively active for these currents, in contrast to the remaining

majority of the class III antiarrhythmic agents that have additional beta or calcium channel

blocking properties.

Hawthorn likely enhances the activity of digitalis, although this remains controversial as

its method of metabolism is currently unknown and as a result its concomitant use should be

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monitored for the development of toxicity.14-15 Hawthorn also inhibits the biosynthesis of

thromboxane A2, and it could potentially increase the risk of bleeding in patients taking

antiplatelets and/or anticoagulant agents.16 Without additional data on metabolism, safety and

efficacy, clinicians should discourage unsupervised use of hawthorn in patients with CHF who

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are taking heart failure medications.

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Khella (Ammi majus)

Khellin, an extract from the fruit of the Khella or Ammi majus plant has long been used

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for non-cardiac ailments in its native region of North Africa. The discovery of the antiarrhythmic

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properties of Khellin resulting in its eventual purification to pharmaceutical grade amiodarone

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was made by the Lebanese physiologist Gleb von Anrep while working in Cairo circa 1946 as

detailed by Dr. Arthur Hollman in the text Cardiology from Nature.17 A technician in his
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laboratory was taking Khella for an unrelated issue and found a coincident relief from his

longstanding anginal symptoms. This observation led to the isolation of Khellin, the active
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component of Khella by Dr. Anrep. Amiodarone was eventually developed in 1961 at the Labaz
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Co. in Belgium, by chemists Tondeur and Binon,18 from preparations of Khellin with subsequent

popularity in Europe as a treatment for angina pectoris.17 With additional investigation by Dr.
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Bramah Singh the antiarrhythmic properties of amiodarone were fully described making it the

first member of a new class of antiarrhythmic agents (eventually becoming class III).19
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As would be expected from its role in the development of amiodarone, Khella extract has
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antiarrhythmic properties similar to those of amiodarone. Little clinical data exist for the use of

Khella either in animals or in humans for antiarrhythmic purposes. It stands to reason that the

action, metabolism, medication interactions, side effects and toxicities of Khella are similar to

those of amiodarone, however these presumed similarities are little more than assumptions as

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they have not been described clinically or experimentally. Khella has been described to cause a

pigmentary retinopathy in wild birds that consume it not unlike that seen with amiodarone

providing some strength to assumed similarities between itself and amiodarone.17

Compared to amiodarone, Khella extract is certainly less potent from an antiarrhythmic

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standpoint but still may possess antiarrhythmic properties along with a risk for currently

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unknown medication interactions and toxicities. Its consumption and possible drug interactions

should be treated the same as amiodarone as we know little about its clinical effects otherwise.

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Barberry (Berberis vulgaris)

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Barberry is a shrub that is common to most areas of temperate Europe, Asia, Africa and

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Northeastern regions of the United States. Both the Barberry fruit and the root are utilized to

make extracts with the root containing a larger proportion of the active alkaloid berberine. Its use
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dates back over 2500 years in Ayurvedic and Chinese medicine as a treatment for fever and

gastrointestinal disorders. Iran is currently the largest producer of Barberry where it is utilized
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commonly as a food seasoning and as an antibacterial, antipyretic, antipruritic and

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antiarrhythmic agent.20

Previous pharmacological studies on berberine, an isoquinoline alkaloid found in the root

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and bark of Berberis vulgaris, demonstrated that it possessed potent vasodilatory21 and

antiarrhythmic activity.22 Its antiarrhythmic activity stems from an associated prolongation of the
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action potential duration through a dose dependent inhibition of Ito.22 Such an effect has been
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shown in animal models and human atrial cells in vitro and is consistent with the antiarrhythmic

effects of disopyramide and quinidine, both class 1A agents. The selective nature of the Ito

blockade with berberine differentiates it from the class IA agents in that it is not accompanied by

inward sodium current inhibition. The resulting prolongation of the action potential is more

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consistent with class III activity and results in longer effective refractory periods.22 Given these

isolated effects on Ito this agent has possible therapeutic potential for Brugada patients as their

loss of function in the INa channel results in unopposed Ito activity. Berberine may provide a

more specific (and possibly more potent) Quinidine like effect on Ito and a similar or larger

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reduction in subsequent ventricular fibrillation and death. Further study is required prior to

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advocating for the use of berberine in such a fashion.

Currently no clinical evidence for its efficacy exists but with its similarities to some class

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1A and or III antiarrhythmic agents it is likely to carry some proarrhythmic effects along with

any potential efficacy. Moreover, berberine has been shown to inhibit CYP3A423-25 similar to the

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action of grapefruit. Such inhibition will increase blood levels of statins, cyclosporine, calcium-
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channel blockers, midazolam, estrogen, and terazosin. The action of these medications is

potentiated by increased bioavailability, which potentially can result in dangerous hypotension,

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myopathy, or liver toxicity. These potential interactions should be discussed with patients taking
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medications metabolized by the CYP3A4 system, and they should be advised to avoid Barberry
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derived products.

Omega–3 Fatty Acids

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Beyond its use in hyperlipidemia, a number of basic and clinical studies have provided

evidence for clinically significant antiarrhythmic properties of omega-3 fatty acids.26-32 The most
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significant data in support of an antiarrhythmic effect of omega-3 fatty acids was found within
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Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)–Prevenzione

trial with a significant reduction in the incidence of sudden death for survivors of myocardial

infarction treated with omega-3 fatty acids.27 Numerous additional investigations have supported

the benefit of fish oil intake for the reduction in serious ventricular arrhythmias.33-35 However,

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the effect of omega-3 supplementation on atrial fibrillation appears marginal and remains an area

of ongoing debate with the majority of data not supporting its efficacy.54-57

The proposed mechanism behind this reduction is an inhibition of the conversion of

omega-6 fatty acids to their proarrhythmic cyclooxygenase metabolites (Figure 1).36-37 The

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majority of experimental studies indicate that omega-3 fatty acids may prevent fatal ventricular

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arrhythmias at least in part by inhibition of voltage-gated sodium channels and maintenance of

L-type calcium channels to prevent calcium overload during stress.37-49 In addition omega-3 fatty

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acids have been shown to prevent or attenuate beta agonist induced arrhythmias in vitro, possibly

supporting a beta blockade like effect.50 However the primary site of action of omega-3 fatty

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acids along with the exact mechanism has not been determined and is an area of active research.
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Medication interactions are of only minor concern with omega-3 fatty acids. Two reports

detail dramatic elevations in INR with concurrent use of warfarin and omega-3 fatty acids that
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improved upon cessation of omega-3 use.58 The proposed mechanism of the transient elevation
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in INR was an eicosapentaenoic acid and docosahexaenoic acid fatty acid induced reduction in
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vitamin K-dependent coagulation factors, although further confirmatory study is required. Given

the volume of omega-3 fatty acid use the volume of described interactions is scant; however
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patients taking warfarin with fish oil should be monitored closely.

Acupuncture
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Acupuncture has been utilized in eastern and Chinese medicine for thousands of years for
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a variety of ailments. Chinese medicine classifies supraventricular arrhythmias, as caused by

Heart Yin deficiency when cardiac structure and function are normal or by Heart Yang

deficiency when accompanied by cardiac abnormalities.59 Stimulation of the Neiguan spot via

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acupuncture, located in the portion of the Meridian of the Heart Minister situated in the forearm

(Fig. 2), has been shown to relieve chest pain and the sensation of palpitations.60

Recent scientific experimental studies have examined the role that acupuncture may have

as an effective intervention for cardiac arrhythmias.59,61-70 Although plagued by methodological

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shortcomings these studies support acupuncture as an effective treatment for atrial

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fibrillation59,67, paroxysmal supraventricular tachycardia62, inappropriate sinus tachycardia68 and

symptomatic premature ventricular contractions.61,65-66,69 Of the available data Lomuscio et al59

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conducted the most rigorous study examining the antiarrhythmic effect of acupuncture. In a

cohort of 80 consecutive patients undergoing cardioversion for persistent atrial fibrillation they

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compared amiodarone therapy to once weekly acupuncture (Neiguan, Shenmen, and Xinshu
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spots) or sham acupuncture for 10 weeks. Through one year of follow up there was no difference

between the acupuncture (27%) and amiodarone (35%) group with regard to recurrence of atrial
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fibrillation. The sham acupuncture group actually had the highest recurrence rates (69%)
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followed by the control group (54%).

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The mechanism behind an antiarrhythmic effect of acupuncture remains unknown.

Experimental evidence does suggest that acupuncture of the Neiguan spot might produce a
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reduction in sympathetic tone as indicated by its effects on heart rate variability in men and on

the hemodynamic parameters in anesthetized open-chest dogs.71-72 In addition, bilateral

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acupuncture of the Neiguan spot has been shown to reduce firing of the amygdala and a
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reduction in sympathetic tone.73 Several clinical and experimental reports have indicated that

disturbance of the autonomic nervous system may favor the initiation and maintenance of AF

episodes. It is therefore possible to speculate that the antiarrhythmic action of acupuncture is

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through modulation of the sympathetic and parasympathetic nervous systems, a possibility that

needs further although this is entirely theory and in need of further study.

Yoga

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Yoga is an ancient discipline designed to bring balance and health to the entire mind,

body and spiritual dimensions of the individual. Yoga is comprised of eight aspects: yama

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(universal ethics), niyama (individual ethics), asana (physical postures), pranayama (breath

control), pratyahara (control of the senses), dharana (concentration), dyana (meditation), and

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samadhi (bliss).74 Although it has been a longstanding popular practice in India, yoga has only

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recently become more common in Western society. In a national, United States population-based

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telephone survey (n = 2055), Saper et al. found 3.8% of respondents reported using yoga in the

previous year with wellness (64%) and specific health conditions (48%) as the motivation for its
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use.75

Through its combination of structured physical exercises, breathing techniques, and

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meditation, Yoga has been shown to positively influence cardiac autonomic function primarily
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due to a reduction in sympathetic tone and circulating catecholamines.76-77 From this observed

effect it is easy to hypothesize a reduction in arrhythmic events in patients with chronic

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arrhythmic disease secondary to the longer refractory periods of myocardial tissue seen with

greater parasympathetic activity.78 Lakkireddy et al. provided confirmatory support of this

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hypothesis in a single center study of 52 consecutive patients with paroxysmal atrial fibrillation;
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where adherence to an hour long twice weekly yoga class compared to their usual activity

resulted in a significant reduction in symptomatic AF episodes.79 Compared to themselves as

controls these patients also experienced a significant improvement in quality of life, anxiety and

depression with yoga when measured via questionnaire data.79

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Figure Legends

Figure 1: The effect of different fatty acids on cardiac arrhythmias.

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AA = arachidonic acid; DMA = docosahexaenoic acid; EPA = eicosapentaenoic acid; LA =

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linoleic acid; LNA = α-linoleic acid (Reproduced with permissions from AJC 37 2013).

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Figure 2: Location of acupuncture points Neiguan, Sharmen and Xinshu (arrows) reproduced

with permissions from JCE59 2013.

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Table 1: CAM therapies with antiarrhythmic properties.

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CAM Antiarrhythmic
Mechanism of Action State of Evidence CAM / Drug Interactions
Therapy Behavior

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Unknown – possible resetting Unknown – possibly
Acupuncture Humans - RCT None
of vagal / sympathetic axis Class II

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CYP3A4 inhibitor: increases statin,
Barberry Reduction in Ito Class IA / III In vitro / Animal Models
cyclosporine levels amongst others.

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Scant – extrapolated from CYP3A4 inducer; decreases tegretol

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Cinchona Reduction in INa Class I
Quinidine evidence levels. “Chincronism”

Digoxin activity; inhibits thrombox.

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Hawthorne Reduction in IKs and IKr Class III In vitro / Animal Models
A2: more bleeding on anticoagulants

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Scant – extrapolated from
Khella Reduction in IKs and IKr Class III Multiple: Similar to Amiodarone
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Increased risk of bleeding on

Motherwort Reduction in If, ICa.L, IK.r Class III In vitro / Animal Models
antiplatelet or anticoagulants.
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Omega-3 Unknown – reduction in Unknown – possibly Rare dramatic elevation in INR with
Humans – RCT
PUFA proarrhythmic fatty acids Class I, II or IV coumadin
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Atrial Selective
Wenxin Keli Reduction in INa In vitro / Animal Models Unknown – Not studied
Class I

Unknown – possible reduction Unknown – possibly

Yoga Humans None
in sympathetic tone Class II
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