Atrial fibrillation is the most prevalent sustained arrhythmia and a major contributor to global morbidity and mortality (Joglar et al., 2024). Epidemiological data suggest that AF burden in the Asia-Pacific region is projected to surpass that of North America and Europe, with the number of AF patients expected to reach 72 million by 2050 (Lippi et al., 2021). As a major population center within the Asia-Pacific, China has seen a twentyfold increase in AF prevalence over the past decade, reaching 1.6% in 2015 (Shi et al., 2022). AF worsens quality of life (QoL) and increases the risk of stroke, heart failure (HF), arrhythmic events, and mortality. Its incidence rises with aging, cardiac dysfunction, comorbidities, and poor lifestyle habits, leading to longer hospital stays, higher costs, and worse outcomes (Kirchhof et al., 2020; Hindricks et al., 2021).

Current AF treatments include pharmacological therapy, catheter ablation, and left atrial appendage occlusion. Pharmacological management primarily consists of antiarrhythmic drugs (AADs) for rhythm or rate control, along with anticoagulants. While pharmacological cardioversion has a success rate of 58%–75%, significant variability and adverse effects limit its widespread use (Dixit et al., 2024; Valembois et al., 2019). Catheter ablation is an effective rhythm-control strategy for drug-refractory symptomatic paroxysmal AF, supported by multiple randomized trials and large registries (Joglar et al., 2024; Schnabel et al., 2023). However, 30%–40% of patients experience recurrence after the first procedure, with recurrence rates up to 45.9% within a year (Joglar et al., 2024). Additionally, thermal injury from radiofrequency ablation can lead to intraoperative pain and postoperative complications, affecting procedural success and patient outcomes. Given the importance of patient selection in determining ablation efficacy (Iliodromitis et al., 2023), it cannot be considered a first-line treatment for all patients, highlighting the need for novel strategies to improve long-term rhythm control, reduce recurrence, and enhance outcomes.

Traditional Chinese Medicine (TCM) offers distinct advantages in treating cardiovascular diseases through its multi-metabolite, multi-target approach. Growing evidence confirms the antiarrhythmic properties of various herbal formulations (Huang et al., 2024; Quan et al., 2023). FLN is a sophisticated hospital preparation developed by Professor Zhongxiang Lin based on decades of specialized clinical experience in arrhythmia management at Longhua Hospital. It is a modified formulation derived from two landmark classical TCM prescriptions—Shengmai San (for nourishing Qi and Yin) and Ganmai Dazao Tang (for emotional regulation and spirit-calming) (National Pharmacopoeia Committee, 2020). Approved for market in China in 2004 (Approval Number: Z20030058), FLN has demonstrated comparable efficacy to propafenone in treating Qi and Yin deficiency-type arrhythmias (Liu et al., 2017; Wei et al., 2017). Clinical studies also report improvements in TCM-related symptoms with a favorable safety profile. A recent study also showed that FLN can reduce the frequency and duration of symptomatic atrial fibrillation episodes and help control ventricular rate (Liu et al., 2023). However, due to limited sample sizes and a lack of robust clinical trials, further investigation is needed.

Metabolomics, as a part of systems biology, is an approach that involves the comprehensive analysis of all metabolites during a specific physiological period (Qiu et al., 2023). With the continuous development of metabolomics, an increasing number of metabolites have been discovered and studied, providing new insights for a deeper understanding of the mechanisms underlying cardiovascular diseases (Lv et al., 2024). This study integrated plasma metabolomics analysis to further explore the mechanism of FLN in treating symptomatic AF. To our knowledge, this is the first randomized double-blind placebo-controlled clinical study combining metabolomics to investigate TCM treatment of symptomatic AF. It provides a new research strategy for exploring the efficacy of TCM and offers scientific reference for understanding the etiology and pathogenesis of Qi-Yin deficiency syndrome in AF treatment with FLN.

This trial is the first randomized, double-blind, placebo-controlled study to evaluate whether oral FLN, combined with conventional medication, can reduce the duration, frequency, and ventricular rate of symptomatic AF. Our findings indicate that FLN significantly decreased AF episodes in patients with paroxysmal AF who had an inadequate response to conventional treatment and also contributed to lower ventricular rates in AF. Additionally, FLN showed good safety and efficacy, with no significant adverse effects. The potential therapeutic benefits may be attributed to its regulation of energy metabolism.

FLN’s therapeutic potential is rooted in its sophisticated integration of TCM principles and modern pharmacological evidence. Developed from the clinical heritage of Professor Zhongxiang Lin, the formula strategically combines Shengmai San and Ganmai Dazao Decoction to achieve a synergistic effect. By addressing both root deficiencies (qi-yin insufficiency) and symptomatic manifestations (heat, stagnation, and emotional imbalance), FLN effectively restores the yin-yang equilibrium essential for managing palpitations. Clinically, FLN has demonstrated promising efficacy in treating various arrhythmias, with an annual usage of approximately 20,000 boxes at Longhua Hospital. Preclinical studies have shown that FLN effectively counteracts aconitine and calcium chloride-induced arrhythmias in rats, potentially through the inhibition of sodium and calcium ion channels (Shen et al., 2013). Further analysis divided FLN into three subgroups—Modified Shengmai San, Modified Ganmai Dazao Decoction, and a simplified FLN formula. All delayed barium chloride-induced arrhythmias and reduced their duration, showing protective effects (Xu et al., 2014). These findings suggest a strong correlation between the formula’s composition and its anti-arrhythmic properties.

In this study, we included symptomatic AF patients, regardless of whether their AF was paroxysmal or non-paroxysmal. Symptomatic AF patients often experience anxiety, depression, and reduced quality of life (Freeman et al., 2015; Heidt et al., 2016). In China, despite the availability of radiofrequency ablation, many patients refuse the procedure due to concerns about surgical trauma or side effects, while others experience AF recurrence post-ablation. Even with standardized Western medicine, AF episodes often remain difficult to control, leading many patients to seek TCM treatment. Notably, our recent study made a compelling observation: despite providing only 1 month of free medication, patients in the treatment group experienced significantly fewer AF episodes and shorter episode durations compared to the control group (P < 0.05) in paroxysmal AF. In patients with permanent AF, FLN also significantly reduced ventricular rates. Furthermore, the treatment group demonstrated improvements in anxiety, depression, and quality of life. These findings suggest that FLN treatment can effectively reduce AF episode frequency and duration while alleviating clinical symptoms. However, we did not observe significant improvements in cardiac function, which may require longer-term clinical follow-up for further validation.

FLN has a strong theoretical foundation supported by both its formulation principles and modern pharmacological research, demonstrating excellent efficacy in arrhythmia management. The formula contains several medicinal botanical drugs such as Kushen, Danshen, Licorice, and Huangqin, all of which have anti-arrhythmic effects (Zhang et al., 2023). The total alkaloids and flavonoids of Kushen exert a “quinidine-like” effect by modulating myocardial potassium and sodium ion channels, reducing excitability, and prolonging the refractory period, thereby inhibiting ectopic pacemaker activity (Liu et al., 2017). In a guinea pig myocardial hypertrophy model, Danshenol II-A reduces the density of fast- and slow-activating delayed rectifier potassium currents in hypertrophic myocardial cells, improving electrophysiological abnormalities (Lu et al., 2022). Licorice has a cardioprotective effect, mainly due to the flavonoid and glycyrrhizin metabolites it contains, both of which have anti-arrhythmic and myocardial cell protective effects (Wang et al., 2025; Wang et al., 2023). The pharmacological studies on these individual botanical drugs provide evidence for the efficacy of FLN in treating arrhythmias. To further explore the potential upstream mechanisms of FLN in treating AF, we conducted a non-targeted plasma metabolomics study.

Emerging evidence links metabolic disorders to AF through electrophysiological and structural remodeling (Watanabe et al., 2008). Conversely, AF itself induces metabolic remodeling, disrupting lipid and ketone metabolism, impairing mitochondrial function, and altering cardiac energy supply (David et al., 2024). Ketone metabolism plays a key role in energy compensation during AF, where high-frequency contractions deplete ATP, prompting increased ketone utilization. As ketone metabolism is more efficient, it reduces oxygen consumption and supports myocardial energy supply (Hariharan et al., 2017). Thus, targeting ketone metabolism—by inhibiting excessive utilization or regulating enzyme activity—may offer a novel therapeutic approach.

Our study suggests that the antiarrhythmic effects of FLN involve a sophisticated recalibration of the metabolic network, particularly centered on butyrate, ketone, and glycerophospholipid metabolism (Zhang et al., 2021). Butyrate undergoes β-oxidation to produce acetyl-CoA, a precursor for ketone synthesis (Ota et al., 2020), and its dysregulation correlates with increased AF risk. Following FLN treatment, we observed a significant downregulation of methyl butyrate and succinate semialdehyde (SAS). As an intermediate in the GABA shunt, the reduction of SAS likely prevents the over-accumulation of metabolic byproducts that trigger oxidative stress, while modulating acetyl-CoA levels to optimize ketone synthesis (Hariharan et al., 2017). Furthermore, the significant upregulation of acylcarnitines—including dodecanoylcarnitine, L-octanoylcarnitine, and decanoylcarnitine—suggests enhanced fatty acid β-oxidation. This is critical for AF therapy, as it indicates a restoration of metabolic flexibility, shifting the heart back toward efficient energy substrates and increasing acetyl-CoA availability for regulated ketone production (Sun et al., 2025). Beyond energy supply, FLN demonstrated a profound impact on protective metabolites. The marked increase in Lutein (a potent antioxidant) and Biliverdin (a cytoprotective agent) suggests that FLN suppresses AF by scavenging reactive oxygen species and mitigating inflammation. Additionally, the enrichment of glycerophospholipid metabolism, evidenced by the upregulation of LysoPC (22:0), points toward the stabilization of the atrial cardiomyocyte membrane, which is essential for preventing electrophysiological leakage and structural remodeling.

In conclusion, these findings indicate that the key metabolites identified in our profiling work regulate AF by integrating energy supply optimization, antioxidant defense, and membrane stabilization. Further exploration of these coordinated mechanisms will provide deeper theoretical support for the clinical application of FLN in AF management.

This study has several limitations. First, the COVID-19 pandemic posed challenges to conducting regular Holter follow-ups and limited patient enrollment, particularly affecting the scalability of a multicenter trial. Second, FLN contains multiple bioactive metabolite botanical drugs whose therapeutic benefits likely arise from synergistic effects. Although a preliminary metabolomic analysis was conducted, further mechanistic studies are warranted to fully elucidate its mode of action.

In conclusion, this randomized clinical trial found that FLN treatment improved the frequency and duration of AF episodes, reduced ventricular rate, and alleviated clinical symptoms in symptomatic AF patients. This study also used metabolomics to explore FLN’s role in AF treatment, providing new insights into TCM-based management.