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. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Review of Complementary and Alternative Medical Treatment of
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Arrhythmias
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Andrew Brenyo MD, Mehmet K. Aktas MD.
Affiliations:
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AJB: Greenville University Health System, Greenville South Carolina MKA: University of Rochester Medical Center, Rochester, New York Grant/Financial Support: None
Address for Correspondence
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Andrew J Brenyo, MD Greenville University Health System Department of Medicine
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701 Grove Road
Greenville, South Carolina 29605
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United States of America
Telephone: (919) 724-7489 Email: [email protected]
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
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the treatment of medical conditions spanning the full spectrum of severity and chronicity. The use of alternative remedies both herbal and others for conditions lacking effective medical
treatment is on the rise. Included within this categorization, arrhythmic disease absent effective
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catheter based therapy or with medical therapy limited by the toxicities of contemporary
antiarrhythmic agents is frequently managed by patients with CAM therapies without their
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practitioner’s knowledge and in the face of potential herb / drug toxicities. This article reviews nine CAM therapies: seven individual herbal therapies along with acupuncture and yoga that 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 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.
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
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number of websites discussing an impressive array of available alternative therapies for
arrhythmias. Many of these complementary and alternative medical (CAM) remedies have antiarrhythmic properties similar to prescription antiarrhythmic agents and if taken
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inappropriately, particularly in combination with prescription antiarrhythmic agents, may prove harmful. Moreover, many CAM therapies can alter the metabolism of other evidence based heart
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failure or antiarrhythmic agents resulting in avoidable toxicity and adverse clinical events. This article reviews the efficacy and safety of CAM therapies (herbal, Yoga and acupuncture) 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 only those identified through the available medical literature are included. CAM’s with Reported Antiarrhythmic Properties
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A list of the discussed CAM agents, their proposed mechanisms and known CAM / drug
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interactions is presented in Table 1. Motherwort (Leonurus Cardiaca)
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 3
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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
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shown to prolong the PR, QRS and QT intervals in rats.1
Further work in isolated rabbit, rat and guinea pig hearts identified the electrophysiologic and related therapeutic effects of Motherwort.2 Prolongation of the activation time constant of If ,
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antagonism of ICa.L, and reductions in the repolarizing current IK.r were observed with
Motherwort preparations both at whole organ and single cell level.2 Such effects at the cellular
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level explain the reduction in sinus rate (If) along with prolongation of the PQ interval (ICa.L, IK.r) seen at the organ level. Its antiarrhythmic activity is similar to class III antiarrhythmic 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 palpitations or as an antiarrhythmic is available. In similar fashion, little is known about the metabolism of the pharmacologically active components of Motherwort. Given its antiplatelet
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effects3, its use should be avoided in any patient on concurrent antiplatelet or anticoagulant therapy and/or those with a bleeding diathesis. As its effects on the cytochrome system remain
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unknown, it should be used with caution in the setting of drugs whose metabolism is cytochrome dependent with narrow therapeutic windows. 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
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Keli to suppress and prevent atrial fibrillation in dog models.4 Within this study the
antiarrhythmic activity of Wenxin Keli occurred through a unique semi selective depression of atrial INa channels and prolongation of the atrial effective refractory period.4 The clinical
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efficacy, metabolism and potential herb / drug interactions in human remains to be studied
agent. Cinchona (Cinchona, various species)
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although its atrial selectivity makes it a very interesting potential pharmaceutical antiarrhythmic
Cinchona bark contains a number of quinone alkaloids, primarily quinine, quinidine, cinchonine, and cinchonidine. Quinine and its stereoisomer quinidine are the most familiar and
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pharmacologically active of these compounds occurring in amounts of 0% to 14% by weight in cinchona bark.5 The use of cinchona bark for the treatment of malarial infections dates back to the 17th century. Its use as an antiarrhythmic was introduced in 1918 by Walter Frey as the
quinidine today.
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“common alkaloid” of cinchona bark and is still used as the purified class 1A antiarrhythmic
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Given that it is the original source of quinidine, any antiarrhythmic effect and possible therapeutic benefit for the treatment of palpitations would be expected to result from the class 1A 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
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interactions with CAM agents.8 With the active ingredients quinine and quinidine having a much better understood and extensive list of medication interactions, the cautious approach would be to assess for any possible interactions with these two agents.
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Hawthorne (Crataegus oxycantha)
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Extract from the berries and flowers of the common Hawthorn plant (Crataegus oxycantha) is a popular herbal supplement widely used by herbalists for treatment of angina, 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 Paracelsus (1493–1541).9 As a contemporary CAM treatment for cardiovascular maladies it
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remains in widespread use today.10
Hawthorn has positive inotropic 11 and vasodilatory effects 12 and in related fashion is thought to increase myocardial perfusion and reduce afterload. Regarding antiarrhythmic effects,
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Hawthorne extract has been shown to prolong the action potential through an inhibition of the inward potassium channels IKs and IKr 13. This effect is similar to that of class III antiarrhythmic
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agents and forms the basis of the antiarrhythmic effects described for Hawthorn extract.13 Of 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
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efficacy, clinicians should discourage unsupervised use of hawthorn in patients with CHF who are taking heart failure medications. Khella (Ammi majus)
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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 properties of Khellin resulting in its eventual purification to pharmaceutical grade amiodarone 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 laboratory was taking Khella for an unrelated issue and found a coincident relief from his
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longstanding anginal symptoms. This observation led to the isolation of Khellin, the active component of Khella by Dr. Anrep. Amiodarone was eventually developed in 1961 at the Labaz Co. in Belgium, by chemists Tondeur and Binon,18 from preparations of Khellin with subsequent
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popularity in Europe as a treatment for angina pectoris.17 With additional investigation by Dr. Bramah Singh the antiarrhythmic properties of amiodarone were fully described making it the
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first member of a new class of antiarrhythmic agents (eventually becoming class III).19 As would be expected from its role in the development of amiodarone, Khella extract has 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
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Compared to amiodarone, Khella extract is certainly less potent from an antiarrhythmic standpoint but still may possess antiarrhythmic properties along with a risk for currently
unknown medication interactions and toxicities. Its consumption and possible drug interactions
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should be treated the same as amiodarone as we know little about its clinical effects otherwise.
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Barberry (Berberis vulgaris)
Barberry is a shrub that is common to most areas of temperate Europe, Asia, Africa and 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 dates back over 2500 years in Ayurvedic and Chinese medicine as a treatment for fever and
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gastrointestinal disorders. Iran is currently the largest producer of Barberry where it is utilized commonly as a food seasoning and as an antibacterial, antipyretic, antipruritic and antiarrhythmic agent.20
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Previous pharmacological studies on berberine, an isoquinoline alkaloid found in the root and bark of Berberis vulgaris, demonstrated that it possessed potent vasodilatory21 and
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antiarrhythmic activity.22 Its antiarrhythmic activity stems from an associated prolongation of the action potential duration through a dose dependent inhibition of Ito.22 Such an effect has been 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
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more specific (and possibly more potent) Quinidine like effect on Ito and a similar or larger reduction in subsequent ventricular fibrillation and death. Further study is required prior to advocating for the use of berberine in such a fashion.
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Currently no clinical evidence for its efficacy exists but with its similarities to some class 1A and or III antiarrhythmic agents it is likely to carry some proarrhythmic effects along with
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any potential efficacy. Moreover, berberine has been shown to inhibit CYP3A423-25 similar to the action of grapefruit. Such inhibition will increase blood levels of statins, cyclosporine, calciumchannel 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 medications metabolized by the CYP3A4 system, and they should be advised to avoid Barberry derived products.
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Omega–3 Fatty Acids
Beyond its use in hyperlipidemia, a number of basic and clinical studies have provided
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evidence for clinically significant antiarrhythmic properties of omega-3 fatty acids.26-32 The most significant data in support of an antiarrhythmic effect of omega-3 fatty acids was found within 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
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omega-6 fatty acids to their proarrhythmic cyclooxygenase metabolites (Figure 1).36-37 The majority of experimental studies indicate that omega-3 fatty acids may prevent fatal ventricular arrhythmias at least in part by inhibition of voltage-gated sodium channels and maintenance of
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L-type calcium channels to prevent calcium overload during stress.37-49 In addition omega-3 fatty acids have been shown to prevent or attenuate beta agonist induced arrhythmias in vitro, possibly
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supporting a beta blockade like effect.50 However the primary site of action of omega-3 fatty acids along with the exact mechanism has not been determined and is an area of active research. 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 in INR was an eicosapentaenoic acid and docosahexaenoic acid fatty acid induced reduction in vitamin K-dependent coagulation factors, although further confirmatory study is required. Given
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the volume of omega-3 fatty acid use the volume of described interactions is scant; however patients taking warfarin with fish oil should be monitored closely.
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Acupuncture
Acupuncture has been utilized in eastern and Chinese medicine for thousands of years for 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
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as an effective intervention for cardiac arrhythmias.59,61-70 Although plagued by methodological shortcomings these studies support acupuncture as an effective treatment for atrial
fibrillation59,67, paroxysmal supraventricular tachycardia62, inappropriate sinus tachycardia68 and
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symptomatic premature ventricular contractions.61,65-66,69 Of the available data Lomuscio et al59 conducted the most rigorous study examining the antiarrhythmic effect of acupuncture. In a
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cohort of 80 consecutive patients undergoing cardioversion for persistent atrial fibrillation they compared amiodarone therapy to once weekly acupuncture (Neiguan, Shenmen, and Xinshu 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%) followed by the control group (54%).
The mechanism behind an antiarrhythmic effect of acupuncture remains unknown.
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Experimental evidence does suggest that acupuncture of the Neiguan spot might produce a reduction in sympathetic tone as indicated by its effects on heart rate variability in men and on
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the hemodynamic parameters in anesthetized open-chest dogs.71-72 In addition, bilateral acupuncture of the Neiguan spot has been shown to reduce firing of the amygdala and a 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.
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Yoga 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
(universal ethics), niyama (individual ethics), asana (physical postures), pranayama (breath
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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 recently become more common in Western society. In a national, United States population-based 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 use.75
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Through its combination of structured physical exercises, breathing techniques, and meditation, Yoga has been shown to positively influence cardiac autonomic function primarily due to a reduction in sympathetic tone and circulating catecholamines.76-77 From this observed
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effect it is easy to hypothesize a reduction in arrhythmic events in patients with chronic arrhythmic disease secondary to the longer refractory periods of myocardial tissue seen with
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greater parasympathetic activity.78 Lakkireddy et al. provided confirmatory support of this hypothesis in a single center study of 52 consecutive patients with paroxysmal atrial fibrillation; 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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48. Leaf A, Kang JX, Xiao YF, Billman GE. n-3 fatty acids in the prevention of cardiac
49. Leaf A, Kang JX, Xiao YF, Billman GE. Dietary n-3 fatty acids in the prevention of cardiac
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arrhythmias. Curr Opin Clin Nutr Metab Care 1998;1:225-228.
evidence. J Intern Med 1996;240:5-12.
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50. Leaf A, Kang JX. Prevention of cardiac sudden death by N-3 fatty acids: a review of the
51. Raitt MH, Connor WE, Morris C, Kron J, Halperin B, Chugh SS, McClelland J, Cook J, MacMurdy K, Swenson R, Connor SL, Gerhard G, Kraemer DF, Oseran D, Marchant C, Calhoun D, Shnider R, McAnulty J. Fish oil supplementation and risk of ventricular tachycardia
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and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. JAMA 2005;293:2884-2891.
52. Schrepf R, Limmert T, Claus Weber P, Theisen K, Sellmayer A. Immediate effects of n-3
1442.
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fatty acid infusion on the induction of sustained ventricular tachycardia. Lancet 2004;363:1441-
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53. Brouwer IA, Zock PL, Wever EF, Hauer RN, Camm AJ, Bocker D, Otto-Terlouw P, Katan MB, Schouten EG. Rationale and design of a randomised controlled clinical trial on supplemental intake of n-3 fatty acids and incidence of cardiac arrhythmia: SOFA. Eur J Clin Nutr 2003;57:1323-1330.
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54. Liu T, Korantzopoulos P, Shehata M, Li G, Wang X, Kaul S. Prevention of atrial fibrillation with omega-3 fatty acids: a meta-analysis of randomised clinical trials. Heart 2011;97:10341040.
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55. Armaganijan L, Lopes RD, Healey JS, Piccini JP, Nair GM, Morillo CA. Do omega-3 fatty acids prevent atrial fibrillation after open heart surgery? A meta-analysis of randomized controlled trials. Clinics (Sao Paulo) 2011;66:1923-1928.
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56. Bianconi L, Calo L, Mennuni M, Santini L, Morosetti P, Azzolini P, Barbato G, Biscione F, Romano P, Santini M. n-3 polyunsaturated fatty acids for the prevention of arrhythmia
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recurrence after electrical cardioversion of chronic persistent atrial fibrillation: a randomized, double-blind, multicentre study. Europace 2011;13:174-181.
57. Kumar S, Sutherland F, Morton JB, Lee G, Morgan J, Wong J, Eccleston DE, Voukelatos J, Garg ML, Sparks PB. Long-term omega-3 polyunsaturated fatty acid supplementation reduces
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the recurrence of persistent atrial fibrillation after electrical cardioversion. Heart Rhythm 2012;9:483-491.
58. Buckley MS, Goff AD, Knapp WE. Fish oil interaction with warfarin. Ann Pharmacother
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2004;38:50-52.
59. Lomuscio A, Belletti S, Battezzati PM, Lombardi F. Efficacy of acupuncture in preventing
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atrial fibrillation recurrences after electrical cardioversion. J Cardiovasc Electrophysiol 2011;22:241-247.
60. Hongwu L. Specific therapeutic effect of Neiguan on heart disease. Int J of Clinical Acupuncture 1998;9:303-305. 61. Liu L. Clinical trial of integrated traditional and western medicine for frequent ventricular premature beat. J Emerg Tradit Chin Med 2005;14:619-621.
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62. Wu R, Lin L. Clinical observation on wrist-ankle acupuncture for treatment of paroxysmal supraventricular tachycardia. Zhongguo Zhen Jiu 2006;26:854–856. 63. Dong S. 32 cases of paroxysmal supraventricular tachycardia in acupuncture Neiguan. J
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Henan Univ Chin Med 2006;21:pp. 69–70.
64. Qi X, Zhao Y. Clinical observation of scalp needling for supraventricular tachycardia. J Acupuncture 1993:34.
beat. Chin J Integr Trad West Med 2002;22:312–313.
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65. Yuan Z, Ai B. Clinical trial of acupuncture plus western medication for ventricular premature
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66. Zhong C. Observation on the efficacy of combined acupuncture and medicine in treating ventricular premature beat organic heart disease. Shanghai J Acu-Mox 2008;27:15-16. 67. Xu H, Zhang Y. Comparison between therapeutic effects of acupuncture and intravenous injection of amiodarone in the treatment of paroxymal atrial fibrillation and atrial flutter.
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Zhongguo Zhen Jiu 2007;27:96-98.
68. Xie H, Li H, Zhao C. Effect of Linggui Bafa acupuncture on heart rate in the patient of sinus tachycardia. Chin Acupunct Moxibust 2004;24:449-451.
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69. Zhang J, Xu W. Frequent ventricular extrasystole treated by needling neiguan (PC 6) plus oral administration of mexiletine—a report of 30 cases. J Tradit Chin Med 2004;24:40-41.
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70. Kim TH, Choi TY, Lee MS, Ernst E. Acupuncture treatment for cardiac arrhythmias: a systematic review of randomized controlled trials. Int J Cardiol 2011;149:263-265. 71. Suming K. Heart rate power spectral analysis during homeostatic action of Neiguan acupoint: Role played by the cardiac vagus nerve. Journal of Traditional Chinese Medicine 1988;8:271276.
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72. Syuu Y, Matsubara H, Kiyooka T. Cardiovascular beneficial effects of electroacupuncture at Neiguan (PC-6) acupoint in anesthetized openchest dog. Jpn J Physiol 2001;51:231-238.
Neiguan in rabbits. J Traditional Chinese Medicine 1991;11:128-138. 74. Iyengar B. Light on Yoga. New York: Schocken Books 1976.
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73. Zhongfang L. Role of amygdaloid nucleus in the correlation between the heart and acupoint
75. Saper RB, Eisenberg DM, Davis RB, Culpepper L, Phillips RS. Prevalence and patterns of
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adult yoga use in the United States: results of a national survey. Altern Ther Health Med 2004;10:44-49.
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76. Khattab K, Khattab AA, Ortak J, Richardt G, Bonnemeier H. Iyengar yoga increases cardiac parasympathetic nervous modulation among healthy yoga practitioners. Evid Based Complement Alternat Med 2007;4:511-517.
77. Selvamurthy W, Sridharan K, Ray US, Tiwary RS, Hegde KS, Radhakrishan U, Sinha KC. A
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new physiological approach to control essential hypertension. Indian J Physiol Pharmacol 1998;42:205-213.
78. Shusterman V, Beigel A, Shah SI, Aysin B, Weiss R, Gottipaty VK, Schwartzman D,
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Anderson KP. Changes in autonomic activity and ventricular repolarization. J Electrocardiol 1999;32 Suppl:185-192.
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79. Lakkireddy D, Atkins D, Pillarisetti J, Ryschon K, Bommana S, Drisko J, Vanga S, Dawn B. Effect of Yoga on Arrhythmia Burden, Anxiety, Depression, and Quality of Life in Paroxysmal Atrial Fibrillation: The YOGA My Heart Study. J Am Coll Cardiol 2013;61:1177-1182.
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Figure 1: The effect of different fatty acids on cardiac arrhythmias.
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Figure Legends
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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with permissions from JCE59 2013.
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Figure 2: Location of acupuncture points Neiguan, Sharmen and Xinshu (arrows) reproduced
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Mechanism of Action
Antiarrhythmic Behavior
State of Evidence
Acupuncture
Unknown – possible resetting of vagal / sympathetic axis
Unknown – possibly Class II
Humans - RCT
None
Barberry
Reduction in Ito
Class IA / III
In vitro / Animal Models
CYP3A4 inhibitor: increases statin, cyclosporine levels amongst others.
Cinchona
Reduction in INa
Class I
Hawthorne
Reduction in IKs and IKr
Khella
Reduction in IKs and IKr
Motherwort
Reduction in If, ICa.L, IK.r
Omega-3 PUFA
Unknown – reduction in proarrhythmic fatty acids
Yoga
Class III
In vitro / Animal Models
Digoxin activity; inhibits thrombox. A2: more bleeding on anticoagulants
Class III
Scant – extrapolated from amiodarone evidence
Multiple: Similar to Amiodarone
Class III
In vitro / Animal Models
Increased risk of bleeding on antiplatelet or anticoagulants.
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CYP3A4 inducer; decreases tegretol levels. “Chincronism”
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CAM / Drug Interactions
Scant – extrapolated from Quinidine evidence
Unknown – possibly Class I, II or IV
Humans – RCT
Reduction in INa
Atrial Selective Class I
In vitro / Animal Models
Unknown – possible reduction in sympathetic tone
Unknown – possibly Class II
Humans
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Wenxin Keli
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CAM Therapy
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Table 1: CAM therapies with antiarrhythmic properties.
Rare dramatic elevation in INR with coumadin Unknown – Not studied None
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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. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Review of Complementary and Alternative Medical Treatment of
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Arrhythmias
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Andrew Brenyo MD, Mehmet K. Aktas MD.
Affiliations:
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AJB: Greenville University Health System, Greenville South Carolina MKA: University of Rochester Medical Center, Rochester, New York Grant/Financial Support: None
Address for Correspondence
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Andrew J Brenyo, MD Greenville University Health System Department of Medicine
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701 Grove Road
Greenville, South Carolina 29605
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United States of America
Telephone: (919) 724-7489 Email: [email protected]
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
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the treatment of medical conditions spanning the full spectrum of severity and chronicity. The use of alternative remedies both herbal and others for conditions lacking effective medical
treatment is on the rise. Included within this categorization, arrhythmic disease absent effective
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catheter based therapy or with medical therapy limited by the toxicities of contemporary
antiarrhythmic agents is frequently managed by patients with CAM therapies without their
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practitioner’s knowledge and in the face of potential herb / drug toxicities. This article reviews nine CAM therapies: seven individual herbal therapies along with acupuncture and yoga that 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 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.
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
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number of websites discussing an impressive array of available alternative therapies for
arrhythmias. Many of these complementary and alternative medical (CAM) remedies have antiarrhythmic properties similar to prescription antiarrhythmic agents and if taken
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inappropriately, particularly in combination with prescription antiarrhythmic agents, may prove harmful. Moreover, many CAM therapies can alter the metabolism of other evidence based heart
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failure or antiarrhythmic agents resulting in avoidable toxicity and adverse clinical events. This article reviews the efficacy and safety of CAM therapies (herbal, Yoga and acupuncture) 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 only those identified through the available medical literature are included. CAM’s with Reported Antiarrhythmic Properties
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A list of the discussed CAM agents, their proposed mechanisms and known CAM / drug
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interactions is presented in Table 1. Motherwort (Leonurus Cardiaca)
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 3
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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
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shown to prolong the PR, QRS and QT intervals in rats.1
Further work in isolated rabbit, rat and guinea pig hearts identified the electrophysiologic and related therapeutic effects of Motherwort.2 Prolongation of the activation time constant of If ,
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antagonism of ICa.L, and reductions in the repolarizing current IK.r were observed with
Motherwort preparations both at whole organ and single cell level.2 Such effects at the cellular
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level explain the reduction in sinus rate (If) along with prolongation of the PQ interval (ICa.L, IK.r) seen at the organ level. Its antiarrhythmic activity is similar to class III antiarrhythmic 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 palpitations or as an antiarrhythmic is available. In similar fashion, little is known about the metabolism of the pharmacologically active components of Motherwort. Given its antiplatelet
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effects3, its use should be avoided in any patient on concurrent antiplatelet or anticoagulant therapy and/or those with a bleeding diathesis. As its effects on the cytochrome system remain
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unknown, it should be used with caution in the setting of drugs whose metabolism is cytochrome dependent with narrow therapeutic windows. 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
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Keli to suppress and prevent atrial fibrillation in dog models.4 Within this study the
antiarrhythmic activity of Wenxin Keli occurred through a unique semi selective depression of atrial INa channels and prolongation of the atrial effective refractory period.4 The clinical
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efficacy, metabolism and potential herb / drug interactions in human remains to be studied
agent. Cinchona (Cinchona, various species)
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although its atrial selectivity makes it a very interesting potential pharmaceutical antiarrhythmic
Cinchona bark contains a number of quinone alkaloids, primarily quinine, quinidine, cinchonine, and cinchonidine. Quinine and its stereoisomer quinidine are the most familiar and
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pharmacologically active of these compounds occurring in amounts of 0% to 14% by weight in cinchona bark.5 The use of cinchona bark for the treatment of malarial infections dates back to the 17th century. Its use as an antiarrhythmic was introduced in 1918 by Walter Frey as the
quinidine today.
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“common alkaloid” of cinchona bark and is still used as the purified class 1A antiarrhythmic
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Given that it is the original source of quinidine, any antiarrhythmic effect and possible therapeutic benefit for the treatment of palpitations would be expected to result from the class 1A 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
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interactions with CAM agents.8 With the active ingredients quinine and quinidine having a much better understood and extensive list of medication interactions, the cautious approach would be to assess for any possible interactions with these two agents.
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Hawthorne (Crataegus oxycantha)
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Extract from the berries and flowers of the common Hawthorn plant (Crataegus oxycantha) is a popular herbal supplement widely used by herbalists for treatment of angina, 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 Paracelsus (1493–1541).9 As a contemporary CAM treatment for cardiovascular maladies it
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remains in widespread use today.10
Hawthorn has positive inotropic 11 and vasodilatory effects 12 and in related fashion is thought to increase myocardial perfusion and reduce afterload. Regarding antiarrhythmic effects,
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Hawthorne extract has been shown to prolong the action potential through an inhibition of the inward potassium channels IKs and IKr 13. This effect is similar to that of class III antiarrhythmic
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agents and forms the basis of the antiarrhythmic effects described for Hawthorn extract.13 Of 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
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efficacy, clinicians should discourage unsupervised use of hawthorn in patients with CHF who are taking heart failure medications. Khella (Ammi majus)
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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 properties of Khellin resulting in its eventual purification to pharmaceutical grade amiodarone 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 laboratory was taking Khella for an unrelated issue and found a coincident relief from his
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longstanding anginal symptoms. This observation led to the isolation of Khellin, the active component of Khella by Dr. Anrep. Amiodarone was eventually developed in 1961 at the Labaz Co. in Belgium, by chemists Tondeur and Binon,18 from preparations of Khellin with subsequent
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popularity in Europe as a treatment for angina pectoris.17 With additional investigation by Dr. Bramah Singh the antiarrhythmic properties of amiodarone were fully described making it the
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first member of a new class of antiarrhythmic agents (eventually becoming class III).19 As would be expected from its role in the development of amiodarone, Khella extract has 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
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Compared to amiodarone, Khella extract is certainly less potent from an antiarrhythmic standpoint but still may possess antiarrhythmic properties along with a risk for currently
unknown medication interactions and toxicities. Its consumption and possible drug interactions
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should be treated the same as amiodarone as we know little about its clinical effects otherwise.
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Barberry (Berberis vulgaris)
Barberry is a shrub that is common to most areas of temperate Europe, Asia, Africa and 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 dates back over 2500 years in Ayurvedic and Chinese medicine as a treatment for fever and
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gastrointestinal disorders. Iran is currently the largest producer of Barberry where it is utilized commonly as a food seasoning and as an antibacterial, antipyretic, antipruritic and antiarrhythmic agent.20
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Previous pharmacological studies on berberine, an isoquinoline alkaloid found in the root and bark of Berberis vulgaris, demonstrated that it possessed potent vasodilatory21 and
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antiarrhythmic activity.22 Its antiarrhythmic activity stems from an associated prolongation of the action potential duration through a dose dependent inhibition of Ito.22 Such an effect has been 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
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more specific (and possibly more potent) Quinidine like effect on Ito and a similar or larger reduction in subsequent ventricular fibrillation and death. Further study is required prior to advocating for the use of berberine in such a fashion.
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Currently no clinical evidence for its efficacy exists but with its similarities to some class 1A and or III antiarrhythmic agents it is likely to carry some proarrhythmic effects along with
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any potential efficacy. Moreover, berberine has been shown to inhibit CYP3A423-25 similar to the action of grapefruit. Such inhibition will increase blood levels of statins, cyclosporine, calciumchannel 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 medications metabolized by the CYP3A4 system, and they should be advised to avoid Barberry derived products.
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Omega–3 Fatty Acids
Beyond its use in hyperlipidemia, a number of basic and clinical studies have provided
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evidence for clinically significant antiarrhythmic properties of omega-3 fatty acids.26-32 The most significant data in support of an antiarrhythmic effect of omega-3 fatty acids was found within 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
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omega-6 fatty acids to their proarrhythmic cyclooxygenase metabolites (Figure 1).36-37 The majority of experimental studies indicate that omega-3 fatty acids may prevent fatal ventricular arrhythmias at least in part by inhibition of voltage-gated sodium channels and maintenance of
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L-type calcium channels to prevent calcium overload during stress.37-49 In addition omega-3 fatty acids have been shown to prevent or attenuate beta agonist induced arrhythmias in vitro, possibly
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supporting a beta blockade like effect.50 However the primary site of action of omega-3 fatty acids along with the exact mechanism has not been determined and is an area of active research. 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 in INR was an eicosapentaenoic acid and docosahexaenoic acid fatty acid induced reduction in vitamin K-dependent coagulation factors, although further confirmatory study is required. Given
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the volume of omega-3 fatty acid use the volume of described interactions is scant; however patients taking warfarin with fish oil should be monitored closely.
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Acupuncture
Acupuncture has been utilized in eastern and Chinese medicine for thousands of years for 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
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as an effective intervention for cardiac arrhythmias.59,61-70 Although plagued by methodological shortcomings these studies support acupuncture as an effective treatment for atrial
fibrillation59,67, paroxysmal supraventricular tachycardia62, inappropriate sinus tachycardia68 and
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symptomatic premature ventricular contractions.61,65-66,69 Of the available data Lomuscio et al59 conducted the most rigorous study examining the antiarrhythmic effect of acupuncture. In a
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cohort of 80 consecutive patients undergoing cardioversion for persistent atrial fibrillation they compared amiodarone therapy to once weekly acupuncture (Neiguan, Shenmen, and Xinshu 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%) followed by the control group (54%).
The mechanism behind an antiarrhythmic effect of acupuncture remains unknown.
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Experimental evidence does suggest that acupuncture of the Neiguan spot might produce a reduction in sympathetic tone as indicated by its effects on heart rate variability in men and on
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the hemodynamic parameters in anesthetized open-chest dogs.71-72 In addition, bilateral acupuncture of the Neiguan spot has been shown to reduce firing of the amygdala and a 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.
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Yoga 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
(universal ethics), niyama (individual ethics), asana (physical postures), pranayama (breath
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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 recently become more common in Western society. In a national, United States population-based 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 use.75
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Through its combination of structured physical exercises, breathing techniques, and meditation, Yoga has been shown to positively influence cardiac autonomic function primarily due to a reduction in sympathetic tone and circulating catecholamines.76-77 From this observed
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effect it is easy to hypothesize a reduction in arrhythmic events in patients with chronic arrhythmic disease secondary to the longer refractory periods of myocardial tissue seen with
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greater parasympathetic activity.78 Lakkireddy et al. provided confirmatory support of this hypothesis in a single center study of 52 consecutive patients with paroxysmal atrial fibrillation; 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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1. Milkowska-Leyck K, Filipek B, Strzelecka H. Pharmacological effects of lavandulifolioside from Leonurus cardiaca. J Ethnopharmacol 2002;80:85-90.
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2. Ritter M, Melichar K, Strahler S, Kuchta K, Schulte J, Sartiani L, Cerbai E, Mugelli A, Mohr FW, Rauwald HW, Dhein S. Cardiac and electrophysiological effects of primary and refined extracts from Leonurus cardiaca L. (Ph.Eur.). Planta Med 2010;76:572-582.
hyperviscosity. Am J Chin Med 1989;17:65-70.
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3. Zou QZ, Bi RG, Li JM, Feng JB, Yu AM, Chan HP, Zhen MX. Effect of motherwort on blood
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4. Burashnikov A, Petroski A, Hu D, Barajas-Martinez H, Antzelevitch C. Atrial-selective inhibition of sodium-channel current by Wenxin Keli is effective in suppressing atrial fibrillation. Heart Rhythm 2012;9:125-131.
5. Remington JP. Remington, the science and practice of pharmacy. Easton, Pa.: Mack Pub. Co.,
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1995:1364.
6. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, et al. Mortality and morbidity in patients receiving encainide,
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Figure 1: The effect of different fatty acids on cardiac arrhythmias.
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Figure Legends
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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with permissions from JCE59 2013.
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Figure 2: Location of acupuncture points Neiguan, Sharmen and Xinshu (arrows) reproduced
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Mechanism of Action
Antiarrhythmic Behavior
State of Evidence
Acupuncture
Unknown – possible resetting of vagal / sympathetic axis
Unknown – possibly Class II
Humans - RCT
None
Barberry
Reduction in Ito
Class IA / III
In vitro / Animal Models
CYP3A4 inhibitor: increases statin, cyclosporine levels amongst others.
Cinchona
Reduction in INa
Class I
Hawthorne
Reduction in IKs and IKr
Khella
Reduction in IKs and IKr
Motherwort
Reduction in If, ICa.L, IK.r
Omega-3 PUFA
Unknown – reduction in proarrhythmic fatty acids
Yoga
Class III
In vitro / Animal Models
Digoxin activity; inhibits thrombox. A2: more bleeding on anticoagulants
Class III
Scant – extrapolated from amiodarone evidence
Multiple: Similar to Amiodarone
Class III
In vitro / Animal Models
Increased risk of bleeding on antiplatelet or anticoagulants.
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CYP3A4 inducer; decreases tegretol levels. “Chincronism”
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CAM / Drug Interactions
Scant – extrapolated from Quinidine evidence
Unknown – possibly Class I, II or IV
Humans – RCT
Reduction in INa
Atrial Selective Class I
In vitro / Animal Models
Unknown – possible reduction in sympathetic tone
Unknown – possibly Class II
Humans
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Wenxin Keli
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CAM Therapy
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Table 1: CAM therapies with antiarrhythmic properties.
Rare dramatic elevation in INR with coumadin Unknown – Not studied None
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