Contemporary medical literature is sparse regarding the safety and efficacy of commonly used nontraditional arrhythmia therapies. In contrast, a cursory Internet search reveals an astounding 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 inappropriately, particularly in combination with prescription antiarrhythmic agents, may prove 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 study 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 interactions of commonly used agents. The agents discussed are far from all inclusive and only those identified through the available medical literature are included.

CAM Agents With Reported Antiarrhythmic Properties

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

Motherwort (Leonurus cardiaca)

Motherwort (L 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 “Mother’s Herb.” Regarding cardiovascular maladies, it has been used for a generic “cardiac debility” and tachycardia or palpitations. Phenylpropanoid glycosides have 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 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 I_f, 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 level explain the reduction in sinus rate (I_f) along with prolongation of the PQ interval (ICa_.L, IK_.r) seen at the organ level. Its antiarrhythmic activity is similar to class 3 antiarrhythmic agents with little effect on phase 0 of the action potential, prolongation of phase 2, and a reduction in I_f resulting in a slowing of the sinus rate.

Currently no data regarding the efficacy and safety of motherwort for the treatment of palpitations or as an antiarrhythmic agent is available. In similar fashion, little is known about the metabolism of the pharmacologically active components of motherwort. Given its antiplatelet effects,³ 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 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 chinensisBatal extract, Codonopsis, notoginseng, amber, and Rhizoma polygonati. In China, it possesses a licensable indication for premature ventricular contractions, which was included in the 2009 revision of the National Reimbursement Drug List.

Recent animal model work by Burashnikov et al⁴ has supported the ability of Wenxin Keli to suppress and prevent atrial fibrillation (AF) in dog models. Within this study, the antiarrhythmic activity of Wenxin Keli occurred through a unique semiselective depression of 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, although its atrial selectivity makes it a very interesting potential pharmaceutical antiarrhythmic agent.

Cinchona (Cinchona, Various Species)

Cinchona bark contains a number of quinone alkaloids, primarily quinine, quinidine, 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 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 “common alkaloid” of cinchona bark and is still used as the purified class 1A antiarrhythmic quinidine today.

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 are 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 previous myocardial infarction.⁶

The only significant medication interaction noted with cinchona is a decrease in systemic levels of carbamazepine through induction of CYP3A4 by way of 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 better understood and extensive list of medication interactions, the cautious approach would be to assess for any possible interactions with these 2 agents.

Hawthorn (Crataegus oxycantha)

Extract from the berries and flowers of the common hawthorn plant (C oxycantha) is a popular herbal supplement widely used by herbalists for the treatment of angina, arrhythmia, hypertension, and congestive heart failure. Its use as a cardiovascular agent in European medicine dates to 1st century Greek herbalist Dioscorides and later Swiss physician Paracelsus (1493 to 1541). ⁹ As a CAM treatment for cardiovascular maladies, it remains in widespread use today. ¹⁰

Hawthorn has positive inotropic¹¹ and vasodilatory effects¹² and, in related fashion, is thought to increase myocardial perfusion and reduce afterload. Regarding antiarrhythmic effects, Hawthorn extract has been shown to prolong the action potential through an inhibition of the inward potassium channels IK_s and IK_r.¹³This effect is similar to that of class 3 antiarrhythmic 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 3 antiarrhythmic agents that have additional β- 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 monitored for the development of toxicity.^14 and 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.¹⁶Without additional data on metabolism, safety, and efficacy, clinicians should discourage unsupervised use of hawthorn in patients with congestive heart failure who are taking heart failure medications.

Khella (Ammi majus)

Khellin, an extract from the fruit of the khella or A majus plant, has long been used for noncardiac 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 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 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 first member of a new class of antiarrhythmic agents (eventually becoming class 3). 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 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 with 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 should be treated the same as amiodarone as we know little about its clinical effects otherwise.

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 used to make extracts with the root containing a larger proportion of the active alkaloid berberine. Its use dates back over 2,500 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 used commonly as a food seasoning and as an antibacterial, antipyretic, antipruritic, and antiarrhythmic agent.²⁰

Previous pharmacologic studies on berberine, an isoquinoline alkaloid found in the root and bark of B vulgaris, demonstrated that it possessed potent vasodilatory ²¹ and antiarrhythmic activity. ²² Its antiarrhythmic activity stems from an associated prolongation of the action potential duration through a dose-dependent inhibition of I_to. 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 I_to blockade with berberine differentiates it from the class 1A agents in that it is not accompanied by inward sodium current inhibition. The resulting prolongation of the action potential is more consistent with class 3 activity and results in longer effective refractory periods. ²² Given these isolated effects on I_to, this agent has possible therapeutic potential for Brugada patients as their loss of function in the INa channel results in unopposed I_to activity. Berberine may provide a more specific (and possibly more potent) quinidine-like effect on I_to and a similar or larger reduction in subsequent ventricular fibrillation and death. Further study is required before advocating the use of berberine in such a fashion.

Currently, no clinical evidence for its efficacy exists but with its similarities to some class 1A and/or 3 antiarrhythmic agents, it is likely to carry some proarrhythmic effects along with any potential efficacy. Moreover, berberine has been shown to inhibit CYP3A4^{23, 24 and 25} similar to the action of grapefruit. Such inhibition will increase blood levels of statins, cyclosporine, calcium channel blockers, midazolam, estrogen, and terazosin. The action of these medications is potentiated by increased bioavailability, which potentially can result in dangerous hypotension, 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.

Omega-3 Fatty Acids

Beyond their use in hyperlipidemia, a number of basic and clinical studies have provided evidence for clinically significant antiarrhythmic properties of omega-3 fatty acids.^{26, 27, 28, 29, 30, 31 and 32} The most significant data in support of an antiarrhythmic effect of omega-3 fatty acids were found in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico–Prevenzione trial with a significant reduction in the incidence of sudden death for survivors of myocardial infarction treated with omega-3 fatty acids.²⁷Numerous additional investigations have supported the benefit of fish oil intake for the reduction in serious ventricular arrhythmias.^{33, 34 and 35} However, the effect of omega-3 supplementation on AF appears marginal and remains an area of ongoing debate with most data not supporting its efficacy.^{36, 37, 38 and 39}

The proposed mechanism behind this reduction is an inhibition of the conversion of omega-6 fatty acids to their proarrhythmic cyclooxygenase metabolites (Figure 1).^40 and 41 Most 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 L-type calcium channels to prevent calcium overload during stress.^{41,42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 and 53} In addition, omega-3 fatty acids have been shown to prevent or attenuate β agonist–induced arrhythmias in vitro, possibly supporting a β blockade–like effect.⁵⁴ 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 international normalized ratio with concurrent use of warfarin and omega-3 fatty acids that improved on cessation of omega-3 use.⁵⁵ The proposed mechanism of the transient elevation in the international normalized ratio was an eicosapentaenoic acid and docosahexaenoic acid fatty acid–induced reduction in vitamin K–dependent coagulation factors, although further confirmatory study is required. Given the volume of omega-3 fatty acid used, the volume of described interactions is scant; however, patients taking warfarin with fish oil should be monitored closely.

Acupuncture

Acupuncture has been used 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.⁵⁶ Stimulation of the Neiguan spot, by way of acupuncture, located in the portion of the Meridian of the Heart Minister situated in the forearm (Figure 2) has been shown to relieve chest pain and the sensation of palpitations.⁵⁷

Recent scientific experimental studies have examined the role that acupuncture may have as an effective intervention for cardiac arrhythmias.^{56, 58, 69, 60, 61, 62, 63, 64, 65, 66 and 67} Although plagued by methodological shortcomings, these studies support acupuncture as an effective treatment for AF,^56 and 64 paroxysmal supraventricular tachycardia,⁵⁹ inappropriate sinus tachycardia,⁶⁵ and symptomatic premature ventricular contractions.^{58, 62, 63 and 66} Of the available data, Lomuscio et al⁵⁶ conducted the most rigorous study examining the antiarrhythmic effect of acupuncture. In a cohort of 80 consecutive patients undergoing cardioversion for persistent AF, they compared amiodarone therapy to once-weekly acupuncture (Neiguan, Shenmen, and Xinshu spots) or sham acupuncture for 10 weeks. Through 1 year of follow-up, there was no difference between the acupuncture (27%) and amiodarone (35%) groups with regard to recurrence of AF. The sham acupuncture group actually had the highest recurrence rates (69%) followed by the control group (54%).

The mechanism behind the antiarrhythmic effect of acupuncture remains unknown. 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 the hemodynamic parameters in anesthetized open-chest dogs.^68 and 69 In addition, bilateral acupuncture of the Neiguan spot has been shown to reduce firing of the amygdala and a reduction in sympathetic tone.⁷⁰ 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 through modulation of the sympathetic and parasympathetic nervous systems, a possibility that is in need of further study.

Yoga

Yoga is an ancient discipline designed to bring balance and health to the entire mind, body, and spiritual dimensions of the subject. Yoga is composed of 8 aspects: yama (universal ethics), niyama (individual ethics), asana (physical postures), pranayama (breath control), pratyahara (control of the senses), dharana (concentration), dyana (meditation), and samadhi (bliss).⁷¹ 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 = 2,055), Saper et al⁷² found that 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.

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.^73 and 74 From this observed 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 greater parasympathetic activity.⁷⁵ Lakkireddy et al⁷⁶ provided confirmatory support for this hypothesis in a single-center study of 52 consecutive patients with paroxysmal AF, in which adherence to an hour-long twice-weekly yoga class compared with their usual activity resulted in a significant reduction in symptomatic AF episodes. Compared with themselves as controls, these patients also experienced a significant improvement in quality of life, anxiety, and depression with yoga when measured by way of questionnaire data.⁷⁶

Disclosures

The authors have no conflicts of interest to disclose.

References