Cardiac arrhythmias pose a significant global burden, resulting in cerebrovascular accidents, myocardial infarction and sudden cardiac death (SCD) (1). The worldwide prevalence of atrial fibrillation (AF), characterized by uncoordinated atrial activation with the consequent deterioration of atrial mechanical function, is 37,574 million cases (0.51% of worldwide population) (2). The prevalence of AF is escalating in middle socio-demographic index countries, and its absolute burden is projected to increase by >60% in 2050, being one of the largest epidemics (2). The prevalence of AF is approximately 0.77% in China, with the mean age of patients being 52.5±22.4 years (3), with a lifetime risk of 1/5 among Chinese adults based on a medical insurance database involving 10 million in Southwest China (4). Premature ventricular contractions (PVCs) manifest from being asymptomatic to the development of cardiomyopathy, heart failure, sustained ventricular tachycardia (VT) or even total mortality. In Europe and North America, 50-100 unexpected SCDs occur per 100,000 population annually, half of these events owing to VT or ventricular fibrillation (VF) (5).

Although classic Western anti-arrhythmics that tend to interact with a specific or single target mostly via inhibition possess potent pharmacologic activity, they portend risks of breaking intracellular stability and have been reported to be arrhythmogenic (6). Consequently, the development of safe and effective regimens remains a major focus of contemporary cardiovascular research. With globalization, an integration of the traditional Chinese and Western medical practices has begun in multiple medical centers (7). In recent years, network pharmacology is an effective approach which can be used to address the association between multiple TCM components and the synergistic effect of drugs on a series of targets. Modern Chinese herbal medicines manufactured according to traditional theory, play a significant role in the treatment of cardiac arrhythmias (8).

Wenxin Keli (WXKL) is a first-state sanctioned Traditional Chinese Medicine (TCM)-based anti-arrhythmic drug (8). It was officially marketed in 1995 as it received new certification issued by the Ministry of Health of the People's Republic of China (9). In China, it possesses a licensable indication for PVCs, which was incorporated in the 2009 revision of the National Reimbursement Drug List (10). As a sole anti-arrhythmic herbal extract in the 2010 revision of Chinese Pharmacopoeia, almost 5 million Asians are currently being administered WXKL for the treatment of ventricular arrhythmias (11). Wenxin Keli is composed of 5 constituents: Nardostachys jatamansi DC (Gansong), Radix Notoginseng (Sanqi), Succinum (Hupo), Polygonatum sibricum (Huangjing) and Codonopsis pilosula (Dangshen) (4,6,12-14). Dangshen, the ‘monarch’ in the regimen, characterized by a sweet flavor, boosts ‘qi’ (nutrients), tranquilizes the mind and relieves palpitations. Huangjing, the ‘minister’ herb, enhances the effects of Dangshen, and also possesses a sweet flavor and fortifies the spleen ‘qi’ to nourish the heart and lungs. The remaining 3 ingredients are assistant herbs. The bitter-flavored Sanqi removes blood stasis, relieves pain and tonifies the system. Hupo, neutral and sweet, pacifies the liver and tranquilizes the mind. Gansong is warm and sweet, relieves depression and regulates the liver and spleen ‘qi’. Its indications include palpitations, dyspnea, fatigue, dizziness, chest tightness and pain, and insomnia to improve the quality of life (9,15).

In a rat model of ischemia-reperfusion (I/R) injury, pre-treatment with WXKL was shown to effectively improve cardiac hemodynamics, accelerate coronary blood flow, enhance myocardial contractility, and reduce the occurrence of arrhythmias (16,17). WXKL reportedly increases coronary blood flow, reduces myocardial oxygen consumption, enhances myocardial compliance, improves myocardial hypoxia tolerance, relieves anterior and posterior cardiac loading, and reduces arrhythmic occurrence (16). The aim of the present review article was to review the effects of WXKL on cardiac electrophysiology and how these can prevent cardiac arrhythmias.

Oxidative stress leads to repolarization and conduction abnormalities, eventually resulting in cardiac arrhythmias (57). ROS abundance increases cardiac fibrosis and hypertrophy and reduces inotropy. Defective antioxidant mechanisms in the diabetic heart (58) are mitochondrial electron leakage, NADPH oxidase and protein kinase C (PKC) activation, nitric oxide synthase uncoupling (59) and a common upstream pathway involving interaction of advanced glycation end-products (AGEs) with their receptor (RAGE) to further promote ROS synthesis (60). The mitochondrial translocator protein (TSPO) links mitochondrial instability to lethal arrhythmias through ROS-induced ROS release (RIRR) (58).

Increased ROS production also activates the unfolded protein response (UPR) that accordingly reduces ion channel functionality and creates repolarization abnormalities (1). It decreases Cx43 protein levels in the cell and perturbs gap junction conduction, resulting in dysrhythmias and SCD. Additionally, intracellular Ca2⁺ homeostasis alters and causes fibrosis (61).

WXKL at at a dose of 3 g/kg has been shown to improve intracellular mitochondrial membrane potential and oxygen consumption in primary atrial fibroblasts by reducing ROS in diabetic rats (62). WXKL has been shown to lead to a recovery of the level of malondialdehyde (MDA), the final product of lipid peroxidation, and superoxide dismutase (SOD) in rats/rabbits subjected to I/R (63). WXKL also improves the secretions of taurine and ketone bodies to overcome I/R-induced oxidative stress (17).

Gap junction proteins, connexins, mediate action potential propagation between cells, coordinate mechanical and electrical activity of heart muscle, and ensure simultaneous cardiac electro-mechanical activity. The age-related down-regulation of atrial Cx43 can facilitate the development of AF in old guinea pig hearts (64) and cause interstitial fibrosis and collagen deposition (65). In a canine model of sympathetic AF, the low expression of Cx43 was shown to be involved in AF by influencing inter-cellular channel conduction (66). Cx43 remodeling is associated with atrial denervation following epicardial GP ablation and this is ameliorated by WXKL (40) (Table I).

Cx43 is the primary gap junction protein that is highly expressed within mammalian ventricular muscle at the intercalated disk. A potential shift in its composition in the ventricular conduction system may contribute to VAs in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) (67). Following MI, 2.7 g/kg WXKL has been shown to protect the ultrastructure of gap junctions within the intercalated disk, alleviate CX43 phosphorylation, increase PKC and miRNA-1 levels, and increase the VF threshold (22) (Table II).

Ca²⁺ plays a key role in the excitation-contraction coupling and the activation of Ca²⁺-dependent signaling pathways. APD prolongation as a result of cardiac hypertrophy may increase the Ca²⁺ entry via ICaL during the long plateau phase resulting in spontaneous sarcoplasmic reticulum (SR) Ca²⁺ release (68).

WXKL has been shown to block ICaL reversibly in a dose-dependent manner at 5 g/l in rabbit ventricular myocytes, in rats with transverse aortic constriction (TAC)-induced heart failure (19) and in an experimental model of Brugada syndrome (24), by causing shift of ICaL activation towards negative potentials (6). In the TAC rat model of heart failure, WXKL was shown to reduce ICaL by facilitating the steady-state inactivation and retarding its recovery (19). In cardiac myocytes from rats with MI, WXKL at 4 g/kg/day was shown to significantly increase both the SR Ca²⁺ content and the calcium transient amplitude (69). WXKL inhibits hypoxia and the hypoxia/reoxygenation-induced increase in diastolic [Ca²⁺]_i and the decrease in Δ[Ca²⁺]_i. The effect of WXKL on ICaL may be attributed to its suppressive effect on [Ca²⁺]_i transients (70). WXKL reduces the transmural dispersion of repolarization and ameliorates calcium mishandling by reducing [Ca²⁺]_i overload among Purkinje cells and in hypoxic/reoxygenated cardiomyocytes at 3 g/l in the treatment of ventricular arrhythmias (12,70). A decrease in both the expression of CaMKII and its phosphorylation at Thr-286 may be the primary mechanism through which WXKL inhibits heart failure and arrhythmia (69).

CaMKII regulates SR Ca release and Ca reuptake (71). It is an upstream regulator of INaL in cardiac myocytes. The CaMKII-dependent phosphorylation of ICaL attenuates its inactivation, increasing the ICaL window current that plays a major role in the generation of EADs (72). Excess CaMKII activity due to HF results in enhanced sympathetic excitation and hyperphosphorylation of the ryanodine receptor (RyR), sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) and phospholamban (PLB) proteins, which predisposes the cardiac myocytes to afterdepolarizations.

WXKL at 4 g/kg/day has been shown to significantly reduce the expression of CaMKII, p-CaMKII (Thr-286) and PLB, and to increase the expression of RyR2 and FKBP12.6 in rats with MI, to inhibit arrhythmia (69). In rats with TAC, the beneficial effects of WXKL and KN93, a pharmacologic tool used to inhibit CaMKII, is attributed to the shortening of APD90 and regulation of the CaMK II signal transduction pathway, markedly decreasing the degree of collagen deposition and improving fibrosis and hypertrophy (14).

Shortened ventricular ER potential, APD, fibrillation threshold, and triggered EAD and DAD by a high sympathetic tone increase the risk of VAs (73). In canine models, the denervated myocardium becomes hypersensitive to norepinephrine indicated by the supersensitive shortening of ERP (74). In patients with long QT syndrome (LQTS), VAs are triggered following a sympathetic burst from either emotional stress or exercise. Experimentally, sympathetic stimulation induces changes in ECG repolarization and the reduction of the fibrillation threshold (75). The ischemic and infarcted myocardium becomes a substrate sensitive to arrhythmia triggers due to the heterogeneity of the sympathetic nervous system innervation contributed by nerve sprouting (76).

Parasympathetic activation, on the other hand, is considered to be anti-arrhythmogenic (77). In rodents, 100% VF episodes were shown to be terminated with vagal nerve stimulation and the efficacy was reduced in the presence of atropine (78,79). The majority of episodes of VF in patients with Brugada syndrome are observed during periods of high vagal tone, such as at rest, during sleep, or from 12 to 6 a.m. (80,81).

The positive inotropic effect exerted by WXKL in right ventricular wedge preparation is likely due principally to an increase in ICaL secondary to the release of catecholamines. The boost in ICaL also contributes to restoration of the action potential dome and suppression of phase 2 reentry and pVT. WK increases ICaL via indirect adrenergic stimulation (24). WXKL induces the release of catecholamines from sympathetic nerve endings at the tissue level exerting a tyramine-like effect (9). These ameliorative actions are accompanied by normalization of the repolarization defects in the epicardial AP and of the ECG by a diminution of the accentuated J waves and ST segment elevation (24). The concentration of WXKL is directly proportional to positive inotropy in wedge preparation, contradicting to that in single myocytes (24). In rabbits with MI, treatment with 817 mg/kg/day WXKL downregulates genes associated with neurohumoral system-endothelin 1 and angiotensin I converting enzyme (53).

Arrhythmia has multiple vulnerable facets that need to be addressed individually for optimal patient management. To date, WXKL has shown promising results in sinus rhythm reversion and maintenance, the reduction of PVCs and the suppression of EADs and DADs in a number of experimental and clinical models via diverse effects on channels chiefly INa, ICaL and Ito, CaMKII and its regulatory pathways, inflammatory mediators and P wave dispersion. Its efficacy in suppressing arrhythmogenesis has been compared to western drugs in several trials and the results have been satisfactory. Its safety profile as compared to severe adverse reactions and proarrhythmic tendencies of other western antiarrhythmics has further validated its promising role. With further identification of roles of gene and proteome-based therapies, second messenger systems, intercellular conduction, NCX inhibition, gating modifiers and ryanodine stabilizers, the scope of managing arrhythmias has expanded as opposed to the sole dependence of ion channel conductance-based therapies. Combining these newer approaches with actions of WXKL under diverse pathologies and circumstances could certainly fill the gaps in treating inherited as well as acquired arrhythmic syndromes.