Research Progress on the Anti-Arrhythmic Mechanisms of Ginseng
Release Date:
2021-06-21
Abstract: Ginseng Panax ginseng As a traditional Chinese medicine, ginseng exhibits notable antiarrhythmic effects. This review summarizes recent advances over the past decade in research on the mechanisms underlying the antiarrhythmic actions of ginseng, ginsenosides, and ginseng-containing proprietary Chinese medicines, focusing on multi-ion channel blockade, suppression of inflammatory responses, inhibition of myocardial fibrosis and remodeling, and modulation of autonomic nervous function. The review aims to provide a reference for experimental studies and clinical applications of ginseng-based traditional Chinese medicines that are both highly effective and low in toxicity for the treatment of arrhythmias.
Ginseng is a plant of the Araliaceae family. Panax ginseng The dried roots and rhizomes of Panax ginseng C. A. Mey. are primarily produced in Northeast China, South Korea, North Korea, Japan, the United States, and eastern Russia. Based on their geographic origin, they are broadly classified as Chinese ginseng, Korean ginseng, and American ginseng. According to the processing method, they can be further categorized as red ginseng, sun-dried ginseng, and sugar-coated ginseng. Ginseng possesses high medicinal value; its major constituents include ginsenosides, polysaccharides, proteins, organic acids, and volatile oils, with ginsenosides being the most important bioactive components. The specific compositional profile of ginseng is presented in Table 1. [2-3] 。
Ginseng is a plant of the Araliaceae family. Panax ginseng The dried roots and rhizomes of Panax ginseng C. A. Mey. are primarily produced in Northeast China, South Korea, North Korea, Japan, the United States, and eastern Russia. Based on their geographic origin, they are broadly classified as Chinese ginseng, Korean ginseng, and American ginseng. According to the processing method, they can be further categorized as red ginseng, sun-dried ginseng, and sugar-coated ginseng. Ginseng possesses high medicinal value; its major constituents include ginsenosides, polysaccharides, proteins, organic acids, and volatile oils, with ginsenosides being the most important bioactive components. The specific compositional profile of ginseng is presented in Table 1. [2-3] 。
2 Inhibit inflammatory response
In cardiomyocytes, the inflammatory response triggered by the release of pro-inflammatory cytokines leads to cellular injury. Following myocardial ischemia-reperfusion (I/R) injury, arrhythmias frequently develop. Nuclear factor κB (NF-κB) is a critical nuclear transcription factor; excessive activation of NF-κB can elicit an inflammatory response in cardiac tissue, resulting in cardiomyocyte damage. [31-32] . Han Zhilong et al. [33] Following I/R, significant increases were observed in ventricular myocardial NF-κB, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), P-selectin, and E-selectin in rats with arrhythmias. Among these, TNF-α and IL-1β exert pro-inflammatory effects, while P-selectin and E-selectin mediate adhesion; all four inflammatory mediators are regulated by NF-κB. Ginsenoside Rg 1 Following treatment, inflammatory responses mediated by NF-κB, TNF-α, IL-1β, P-selectin, and E-selectin, as well as elevations in cardiac enzyme markers such as creatine kinase (CK), creatine kinase isoenzyme MB (CK-MB), and lactate dehydrogenase (LDH), were attenuated, thereby improving arrhythmias in rats after ischemia/reperfusion (IR) (Figure 2). In clinical studies, Shenmai injection, when used in combination with amiodarone in 64 patients with acute paroxysmal ventricular arrhythmias, enhanced therapeutic efficacy and was associated with reductions in serum levels of IL-6, TNF-α, and high-sensitivity C-reactive protein (hs-CRP). [34] Shenfu Injection was administered to 120 patients with bradyarrhythmias and was found to significantly reduce levels of IL-6, TNF-α, and high-sensitivity C-reactive protein (hs-CRP), with greater efficacy at higher doses, thereby protecting the myocardium from injury. [35] 。
3 Inhibition of myocardial fibrosis and cardiac remodeling
In studies on post-myocardial infarction atrial fibrillation, Fumai Granules, with ginseng as the principal herb, significantly reduced the incidence and duration of atrial fibrillation, effectively decreased the area of left atrial fibrosis, markedly attenuated type I collagen deposition, increased the expression of Cx43 and Cx40, lowered serum levels of IL-6, MCP-1, TNF-α, and BNP, reduced the levels of myofibroblast-specific markers α-smooth muscle actin (α-SMA), TGF-β1, and MMP9, elevated TIMP-1 levels, and inhibited the differentiation of cardiac fibroblasts into myofibroblasts. [43] . Ma et al. [44] It has been found that Shensong Yangxin Capsules can reduce the degree of left atrial fibrosis, downregulate the expression of TGF-β1, MMP-9, and type I and type III collagen, and inhibit the differentiation of cardiac fibroblasts into myofibroblasts, thereby decreasing the susceptibility to atrial fibrillation following myocardial infarction in rats. When administered to rats with cerebral ischemia and those with myocardial infarction, respectively, aqueous decoctions of American ginseng and Shengmai Injection both significantly increase the expression of ventricular Cx43 protein, improve myocardial remodeling, and reduce the incidence of arrhythmias. [45-46] . Studies have shown that ginsenoside Rb 1 Increasing the expression of Cx43 protein ameliorates doxorubicin-induced heart failure, while ginsenoside Re inhibits angiotensin II–induced atrial gap junction remodeling by upregulating the expression of both Cx40 and Cx43 proteins. [47-48] , thereby inferring ginsenoside Rb 1 Both Re and its derivatives can exert antiarrhythmic effects by inhibiting cardiac remodeling (Figure 3).
4 Regulate the autonomic nervous system
Research on the regulation of arrhythmias through modulation of the autonomic nervous system has been relatively well established for Shenxian Shengmai Oral Liquid and Shensong Yangxin Capsules (Figure 4). Shenxian Shengmai Oral Liquid upregulates FK506-binding protein 12.6 (FKBP12.6), thereby restoring its binding to ryanodine receptor 2 (RyR2), stabilizing RyR2 channel function, and increasing the expression of sarco-endoplasmic reticulum ATPase 2a (SERCA2a), which restores calcium storage in the sarcoplasmic reticulum and consequently increases heart rate. Acetylcholinesterase (AchE-1) is primarily located at the neuromuscular junction, where it hydrolyzes the neurotransmitter acetylcholine (Ach); nicotinic acetylcholine receptors (nAChRs) can form Ach-gated ion channels both pre- and postsynaptically at the neuromuscular junction. Shenxian Shengmai Oral Liquid increases the expression of AchE-1, thereby reducing CHRNA2 Gene expression inhibits cardiac parasympathetic neurotransmission, thereby increasing myocardial contractility and heart rate. [50] . Zhao et al. [51] It has been found that prolonged intermittent atrial fibrillation can lead to enhanced sympathetic nervous activity and reduced vagal activity. Shenxian Shengmai Oral Liquid can decrease sympathetic nerve activity and excessive sympathetic innervation of the atria in dogs subjected to long-term intermittent atrial pacing, while increasing vagal activity; it also reduces tyrosine hydroxylase (TH)—a marker of sympathetic nerves—and lowers both low-frequency (LF) power—associated with sympathetic tone or autonomic balance—and the LF/HF ratio, an index of the interaction between sympathetic and vagal activities, while increasing high-frequency (HF) power, a marker of parasympathetic tone. Consequently, it elevates α7nAChR and acetylcholine levels in the canine atrium, downregulates the expression of the pro-inflammatory cytokines TNF-α and IL-6, thereby suppressing the AERP reduction induced by atrial fibrillation and reducing both the frequency and duration of atrial fibrillation episodes.
5 Conclusion and Outlook
Ginseng, revered as the “King of Herbs,” has a medicinal history spanning over a millennium. In modern times, it is widely used for the prevention and treatment of arrhythmias due to its remarkable pharmacological effects (Table 2), minimal toxic side effects, and extensive clinical application. This review summarizes extensive and in-depth research conducted over the past decade by numerous domestic and international experts on ginseng’s anti-arrhythmic properties. The findings indicate that: (1) the anti-arrhythmic actions of ginseng are predominantly mediated through synergistic interactions. Among these, studies on traditional Chinese patent medicines containing ginseng are particularly abundant; for example, Shensong Yangxin Capsules comprise 12 herbal ingredients and exert effects such as tonifying qi and nourishing the heart, promoting blood circulation and unblocking the meridians, as well as clearing the heart and calming the spirit. The combined use of these individual herbs demonstrates good efficacy against various types of arrhythmias, especially those associated with autonomic dysfunction. As for ginsenosides, most studies have focused on their monotherapy; however, combination therapy has also been explored, such as the concurrent administration of ginsenoside Re and Rg. 1 The inhibitory effect on L-type calcium channels is stronger than that of ginsenoside Re or Rg used alone. 1 [10] . Among ginsenosides, the triterpenoid saponins Re and Rg 1 , Rg 2 and diol-type saponin Rb 1 (1) Rd has been extensively and thoroughly studied, with well-defined pharmacological actions; however, most studies have employed cell or animal models, and no human studies have been reported. Therefore, the development of individual ginsenosides as therapeutic agents for arrhythmias warrants further investigation. (2) The mechanisms underlying ginseng’s anti-arrhythmic effects are primarily attributed to the modulation of multiple ion channels—namely calcium, potassium, and sodium channels—and the consequent alteration of their electrophysiological properties, with particular emphasis on calcium channels, as exemplified by ginsenoside Re and ginsenoside Rg. 1 The mechanisms underlying the antiarrhythmic effects have been the most extensively studied. In addition, some research has also focused on anti-inflammatory pathways, prevention of cardiac remodeling, and modulation of autonomic nervous function. Analysis of these mechanistic studies reveals intrinsic interconnections among different signaling pathways. For instance, proinflammatory cytokines such as TNF-α and IL-6 can induce changes in fibrosis and cardiac remodeling, while fibrosis and cardiac remodeling, in turn, can alter ion channel function. [55] (3) The same saponin can exert multi-target effects, and patent Chinese medicines containing ginseng also exhibit multi-target and multi-pathway actions. For example, ginsenosides Re and Rb. 1 By inhibiting voltage-dependent sodium channel, transient outward potassium channel, and inward rectifier potassium channel currents in ventricular myocytes. [10,15,20] and exerts antiarrhythmic effects by modulating the expression of Cx43 protein. [47-48] ; Mechanistic studies on Shensong Yangxin Capsules have revealed that they exert varying degrees of blockade on ventricular myocyte ion channels, including L-type calcium channel current, sodium channel current, slow-activating delayed rectifier potassium current, and inward-rectifying potassium current. [18-19] Moreover, it also exerts effects on autonomic nervous system modulation, myocardial fibrosis, and cardiac remodeling; notably, anti-inflammatory pathways are involved in inhibiting myocardial fibrosis and modulating autonomic nervous activity. [44,51] 。
In summary, ginseng exhibits anti-arrhythmic effects with minimal toxic side effects and remarkable therapeutic efficacy, giving it certain advantages. However, its complex compositional profile results in multiple targets and a complicated mechanism of action, with numerous gaps in our understanding. While the individual constituents of ginseng have relatively well-defined targets, their clinical application remains limited and warrants further development. Moreover, there is considerable potential for advancing the integration of traditional Chinese medicine and Western medicine, which requires further exploration. For example, Shenmai injection can be used as an adjunct to amiodarone in the treatment of paroxysmal ventricular arrhythmias. [34] Combination therapy can reduce the toxic and adverse effects of Western medicines, enhance the therapeutic efficacy of traditional Chinese medicine, and offer a “Chinese solution” for advancing the international application of TCM in the treatment of arrhythmias.
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