AS-IV is classified as a pentacyclic triterpenoid compound. It is a cyclic derivative of astragaloside, with β-D-xylopyranosyl and β-D-glucopyranosyl residues attached at the O-3 and O-6 positions, respectively (Xu et al., 2023). AS-IV is a white powder with the molecular formula C₄₁H₆₈O₁₄ and a relative molecular weight of 784.97. Its CAS registry number is 84687–43-4, and it has a melting point between 299°C and 300°C when dissolved in methanol. Structurally, AS-IV shares similarities with steroid drugs, characterized by an extremely low aqueous solubility. It demonstrates high solubility in polar organic solvents such as methanol, ethanol, and acetone, while its solubility is significantly reduced in weakly polar organic solvents like chloroform or ethyl acetate (Tan et al., 2020).

AS-IV demonstrates pronounced linear pharmacokinetic properties in preclinical studies. Research has shown that the area under the concentration-time curve (AUC) correlates linearly with the administered dose, and no significant differences in the pharmacokinetics of AS-IV have been observed between rats and Beagle dogs (Zhang et al., 2007). Clinical studies further support these findings, reporting mean maximum plasma concentrations (Cmax) of AS-IV at 2.12, 3.59, 3.71, and 5.17 μg/mL following single doses of 200, 300, 400, and 500 mL of astragaloside injection (AI), respectively (Xu et al., 2013). Corresponding AUC values (AUC(0-∞)) were measured at 4.38, 9.75, 13.59, and 18.22 μg h/mL, while elimination half-lives (t1/2) were recorded as 2.14, 2.59, 2.62, and 2.69 h. In repeated-dose studies, Xu et al. (2013) reported no significant variations in key pharmacokinetic parameters—peak time (Tmax), t1/2, and AUC—between Day 1 and Day 7, suggesting stable pharmacokinetics with prolonged administration. Following a 500 mL dose of AI, 3.91% of the administered AS-IV was excreted in the urine within a 24-h period (Xu et al., 2013). Co-administration with other compounds has been shown to enhance AS-IV pharmacokinetics. For example, interaction with atractylenolide I led to increased oral Cmax and systemic plasma exposure of AS-IV (Song et al., 2014).

The content of AS-IV in Radix Astragali varies significantly depending on its source (Liu et al., 2009), and sample preparation methods also impact its concentration (Monschein et al., 2013). In vivo experiments have categorized 5 mg/kg/day as a moderate dose, while 10 mg/kg/day and 2.5 mg/kg/day are considered high and low doses, respectively (Zhang and Chen, 2013). Effective dosages reported across studies differ; for example, administration of AS-IV at 0.3 and 1.0 mg/kg/day improved cardiac function in a rat model of heart failure (Zhao et al., 2009). Additionally, Qiu et al. (2010) demonstrated that AS-IV at 50 and 100 mg/mL significantly improved the function of homocysteine-induced human umbilical vein endothelial cells by reducing reactive oxygen species (ROS) accumulation and increasing superoxide dismutase (SOD) activity (Qiu et al., 2010). (see Table 1)

Meta-analyses have shown that AS-IV provides significant cardioprotective effects by reducing cardiac preload and afterload and inhibiting cardiac hypertrophy, with an effective therapeutic dose range of 10–80 mg/kg/day (Zhang et al., 2023). A potential nonlinear positive correlation between dosage and therapeutic efficacy has also been suggested (Zhang et al., 2023). Furthermore, AS-IV’s cardioprotective effects in heart failure appear to be dose-dependent, as demonstrated by increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE)-dependent genes, such as heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase 1 (NQO-1), and sulfiredoxin-1 (Srxn-1), with rising AS-IV concentrations in the oxygen-glucose deprivation model (Gu et al., 2015). Animal studies confirm that AS-IV exhibits no evident toxicity or adverse effects within a safe dose range, equivalent to 35–70 times the human dose (Yu et al., 2007).

A pharmacokinetic study in 2013 investigated AS-IV’s tolerability among healthy Chinese participants following single and multiple intravenous infusions of AI. The Cmax of AS-IV after administration of 200, 300, 400, and 500 mL was 2.12, 3.59, 3.71, and 5.17 μg/mL, respectively (Xu et al., 2013). The AUC(0-∞) values were 4.38, 9.75, 13.59, and 18.22 μg h/mL, and the elimination t1/2 averaged 2.14, 2.59, 2.62, and 2.69 h, respectively (Xu et al., 2013). Within 24 h of administering 500 mL of AI, cumulative urinary excretion of AS-IV reached 3.91%, indicating linear pharmacokinetics within a 200–500 mL dose range, with no accumulation observed following once-daily administration of AI (Xu et al., 2013). Additionally, another study reported that following intravenous injection, the primary distribution of Astragaloside IV occurred in the lungs, kidneys, heart, stomach, and spleen, which may reflect the selective uptake of the compound by these organs (Ya et al., 2019).

Caution is advised in pregnant women, as fetotoxic effects have been documented in rats and rabbits at doses exceeding 0.5 mg/kg, though no teratogenic effects have been observed (Jiangbo et al., 2009).

The oral bioavailability of AS-IV is notably low, with studies showing it to be 2.2% in rats (Gu et al., 2004) and 7.4% in Beagle dogs (Zhang et al., 2007). This limited bioavailability is primarily attributed to AS-IV’s relatively large molecular weight, low lipophilicity, and poor intestinal permeability, resulting in suboptimal efficacy for single oral administrations (Artursson and Karlsson, 1991). However, strategies to enhance the oral bioavailability of AS-IV have shown promise. For instance, the AS-IV inclusion complex demonstrated increased bioavailability in rats, with values reaching 10.2%–11.2%, compared to 3.2% for an aqueous solution (Jun-Xian et al., 2011). Complexation with 2-hydroxypropyl-β-cyclodextrin also significantly enhanced AS-IV bioavailability in rats (Chen and Gu, 2009).

Additionally, derivatives of AS-IV, such as LS-102, have shown enhanced pharmacological activity at comparable concentrations (Li Z. et al., 2022). Another derivative, HHQ16, exhibited substantial efficacy in improving cardiac function, notably increasing the left ventricular ejection fraction (LVEF) and left ventricular shortening fraction (LVFS) at a dose of 10 mg/kg. Its effects were observed to surpass those of commonly used drugs, including enalapril and LCZ696 (Wan et al., 2023). However, it is important to note that these findings are largely limited to animal studies, and clinical evidence remains scarce. These observations highlight the challenges associated with AS-IV’s oral administration and underscore the potential of formulation strategies in enhancing its therapeutic efficacy.

I/R injury remains a significant challenge in myocardial reperfusion therapy. The resultant myocardial cell damage and electrophysiological alterations are strongly predisposed to triggering arrhythmias, particularly ventricular arrhythmias such as premature ventricular beats, ventricular tachycardia, and ventricular fibrillation. These conditions can lead to severe hemodynamic disturbances and, in extreme cases, sudden cardiac death (Dauerman and Ibanez, 2021). A growing body of evidence suggests that AS-IV exerts protective effects against cardiac I/R injury through various mechanisms, including enhancing circulation, preventing cellular apoptosis, mitigating oxidative stress, and exerting anti-inflammatory actions (Zheng et al., 2018). A comprehensive meta-analysis demonstrates that AS-IV significantly improves LVEF, reduces left ventricular end-diastolic pressure, downregulates myocardial creatine kinase and troponin expression, optimizes ST segment depression, and minimizes the MI area (Zheng et al., 2018). Furthermore, Shi et al. (2021) revealed that AS-IV alleviates hemodynamic abnormalities in rats with acute MI by suppressing the deposition of type I and type III collagen and regulating myocardial hydroxyproline levels (Shi et al., 2021).

He et al. (2022) have shown that AS-IV enhances ATP production through activation of the insulin-like growth factor 1 receptor signaling pathway. This process reduces endothelial junction protein expression, thereby mitigating albumin leakage from endothelial cells and reducing white blood cell infiltration after I/R, which alleviates cellular edema and enhances coronary vascular endothelial barrier integrity, as well as minimizing microvascular leakage (He et al., 2022). In a rat myocardial I/R model, AS-IV administration significantly improved left ventricular systolic pressure, FS, and EF, while decreasing left ventricular end-diastolic pressure. Moreover, serum lactate dehydrogenase and creatine kinase levels were significantly reduced, and the heart-to-body weight ratio and MI area were also decreased. The primary mechanism underlying these effects involves AS-IV’s ability to increase phosphorylation of PI3K/AKT and GSK-3β proteins, thereby activating the PI3K/AKT/GSK-3β signaling pathway to protect cardiomyocytes from apoptotic damage induced by I/R (Wei et al., 2019).

In an in vitro H9c2 cell model subjected to hypoxia/reoxygenation, AS-IV upregulated the expression of GATA-binding protein 4 (GATA-4), Bcl-2, and P62, while downregulating apoptosis and autophagy-associated genes such as PARP, caspase-3, and Beclin-1. These findings suggest that AS-IV inhibits apoptosis and autophagy in H9c2 cells exposed to I/R. Notably, the expression of GATA-4 was shown to enhance the interaction between Bcl-2 and Beclin-1 under I/R stress, which may contribute to cell survival (Yang et al., 2020). Additionally, another study demonstrated that AS-IV upregulates p-Akt/Akt and Bcl-2 expression in a concentration-dependent manner while downregulating pro-apoptotic proteins such as Bax and caspase-3, thereby mitigating I/R-induced apoptosis (Jia-lin et al., 2017).

I/R injury induces intense local and systemic inflammatory responses, which exacerbate tissue damage and impede left ventricular recovery (Algoet et al., 2023). Studies indicate that AS-IV significantly suppresses the TLR4/NF-κB signaling pathway and downregulates the expression of inflammatory cytokines such as TNF-α and IL-1β. Furthermore, AS-IV administration reduces the expression of Caspase-3 and Bax while enhancing Bcl-2 levels. These effects correlate with a reduction in infarction size and alterations in myocardial morphology, suggesting that AS-IV’s anti-apoptotic effects in the early stages of reperfusion contribute to mitigating subsequent myocardial necrosis. These findings imply that AS-IV counteracts inflammation-mediated cell apoptosis induced by I/R (Lu M. et al., 2015).

Oxidative stress plays a pivotal role in the pathogenesis of myocardial I/R injury (Peoples et al., 2019). During myocardial reperfusion following ischemia, the production of oxygen free radicals increases dramatically, disrupting oxidative balance and antioxidant defense systems, leading to cellular damage and abnormal immune responses (Eltzschig and Eckle, 2011). Jiang et al. (2019) demonstrated that AS-IV activates the Keap1/Nrf2 antioxidant pathway by downregulating Keap1 expression in the cytoplasm, promoting dissociation of Keap1 from Nrf2, facilitating Nrf2 release and translocation to the nucleus, where it binds Maf to initiate the transcription of the antioxidant gene HO-1. This activation scavenges ROS, reduces the consumption of metabolic substrates like succinate, and mitigates excessive ROS production and lipid peroxidation, thereby exerting an antioxidant effect on the myocardium (Jiang et al., 2019).

Mitochondrial dysfunction is a hallmark of myocardial I/R injury, with impaired mitochondrial quality control serving as a critical factor in arrhythmia development (Bai et al., 2023). Studies have shown that after I/R injury, a reduction in ATP 5D protein and its mRNA occurs, leading to decreased ATP/ADP and ATP/AMP ratios, elevated levels of P-MLC2 and serum cTnI, and subsequent cardiac dysfunction. These changes can be significantly alleviated by pretreatment with AS-IV (Tu et al., 2013). Chen et al. (2021) demonstrated that AS-IV derivative LS-102 protects left ventricular function in I/R rats, reducing arrhythmia incidence and infarct size. The mechanism involves activation of the PI3K/Akt/GSK-3β signaling pathway, which reduces Drp1 phosphorylation at Ser616 while enhancing its phosphorylation at Ser637, thereby inhibiting Drp1-mediated mitochondrial fission. This prevents mitochondrial fragmentation, promotes mitochondrial elongation, and preserves mitochondrial structural integrity and function. Additionally, LS-102 stabilizes mitochondrial membrane potential, reduces the Bax/Bcl-2 ratio, and suppresses Caspase-3 expression, thereby alleviating mitochondrial fission-mediated apoptosis (Chen et al., 2020).

In conclusion, AS-IV mitigates cardiac I/R injury through multiple molecular mechanisms, including anti-apoptotic, anti-inflammatory, antioxidant, and mitochondrial protective effects. These actions collectively reduce the incidence of arrhythmias and improve myocardial recovery post-I/R.

Myocardial fibrosis is a prominent pathological alteration observed in numerous cardiovascular diseases, serving as a critical pathophysiological mechanism in cardiac remodeling. Upon injury to cardiomyocytes, fibroblasts proliferate extensively and differentiate into myofibroblasts, which subsequently secrete significant amounts of collagen. This excessive deposition of extracellular matrix (ECM) proteins leads to abnormal accumulation, reducing myocardial compliance, increasing cardiac stiffness, and ultimately impairing cardiac function (Kong et al., 2014). Atrial fibrosis is recognized as a structural remodeling marker associated with arrhythmogenesis (Scholz et al., 2019). Studies indicate that excessive collagen deposition promotes atrial tissue fibrosis, which disrupts the propagation of myocardial impulses and raises the risk of arrhythmia (Akhurst and Hata, 2012).

Research has demonstrated that AS-IV significantly alleviates cardiac hypertrophy and fibrosis induced by MI in mice. The underlying mechanism involves AS-IV’s ability to reduce mitochondrial ROS in myocardial cells of MI mice, inhibit NLRP3 inflammasome activation, and subsequently downregulate the expression of downstream inflammatory factors such as IL-18 and IL-1β, along with the caspase-1 regulator involved in cell pyroptosis. This modulation alters the expression of the key structural region of GSDMD-N in cell pyroptosis, thereby effectively improving MI-induced cardiac hypertrophy and fibrosis (Zhang et al., 2022). Furthermore, Chen et al. found that AS-IV can activate the Nrf-2/HO-1 signaling pathway, suppressing the expression of downstream inflammatory factors like IL-1β and IL-18, mitigating the DOX-induced inflammatory response, and reducing the extent of myocardial fibrosis (Chen et al., 2023).

TGF-β1 is widely acknowledged as a potent inducer of collagen production by cardiac fibroblasts (Euler-Taimor and Heger, 2006), playing a crucial role in myocardial hypertrophy and fibrosis by activating fibroblasts and promoting collagen synthesis (Annes et al., 2003). Chen reported that AS-IV can inhibit the expression of Smads2/3, particularly Smad4, thus blocking TGF-β1 downstream signaling and down-regulating procollagen gene expression. This results in decreased synthesis of ECM components, significantly reducing abnormal collagen deposition in myocardial tissue and substantially reversing myocardial hypertrophy and fibrosis (Chen et al., 2011). Further research by Yang et al. revealed that AS-IV inhibits the TRPM7/TGF-β/Smads signaling pathway, reduces TRPM7 current, lowers calcium ion activity, and thereby attenuates the progression of myocardial fibrosis (Wei et al., 2020). Intriguingly, Du et al. found that gut microbiota alterations are closely related to cardiac fibrosis. Their study showed that AS-IV enhances the abundance of gut microbiota such as Akkermansia, Defluviitaleaceae_UCG-011, and Rikenella in ISO-induced heart failure model mice. This modulation decreases the metabolism of the cardiovascular risk factor phenylalanine, ultimately reducing myocardial collagen deposition, lowering the cardiac weight index, slowing the progression of myocardial fiber thickening and necrosis, and preventing and ameliorating ISO-induced myocardial fibrosis (Du et al., 2022).

Oxidative stress and inflammatory processes accelerate the development of atrial fibrosis, leading to increased collagen deposition and structural remodeling of the atria. These alterations impact the functionality of various ion channels, including hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, L-type calcium channels, sodium channels, and potassium channels. Such channel modifications alter ion flow, transmembrane potential, and reduce both APD and conduction velocity, ultimately disrupting cardiac electrophysiological activity and elevating the risk of arrhythmias (Karam et al., 2017).

The HCN channel, also known as the If channel, is activated near the end of the repolarization phase, enabling inward currents mediated by Na⁺ and K⁺ throughout diastolic depolarization (Rivolta et al., 2020). HCN4 is a primary component of the sinoatrial node current, accounting for 70%–80% of the If current, and is implicated in various cardiovascular conditions, including sinoatrial node dysfunction and arrhythmias (Baruscotti et al., 2010; Schweizer et al., 2014). Liu et al. reported that AS-IV can enhance the If current density in I/R-injured sinoatrial node cells, shorten APD at 20% and 50% repolarization in SAN cells, and upregulate HCN4 expression, thus helping maintain cell volume and cytoskeletal integrity in SAN cells, with potential therapeutic effects for sick sinus syndrome (Liu et al., 2018).

Calcium ion imbalance is a key contributor to the onset and progression of arrhythmia (Deo et al., 2017). Meng et al. demonstrated that AS-IV reduces ROS accumulation in ISO-induced cardiomyocytes, mitigates mitochondrial membrane damage, counters Ca²⁺ redistribution due to oxidative stress, inhibits calpain-1 activation, maintains calcium homeostasis, and prevents apoptosis in ISO-induced myocardial hypertrophy, reducing arrhythmia risk (Mei et al., 2015). Zhang et al. showed that AS-IV activates the cAMP/PKA pathway, increasing phospholamban (PLN) phosphorylation at Ser16 and relieving PLN-mediated inhibition of sarcoplasmic reticulum Ca²⁺ ATPase 2a, thereby reducing spontaneous Ca²⁺ release in post-I/R mice and lowering the risk of AF (Zhang et al., 2012). Zhao et al. reported that AS-IV reduces the amplitude of L-type Ca²⁺ current in guinea pig ventricular cells in a concentration-dependent manner, influencing L-type Ca²⁺ channel kinetics, suppressing channel activity, and blocking Ca²⁺ current, while concurrently inhibiting K⁺ current to prolong APD (Zhao et al., 2013). Lu et al. revealed that AS-IV inhibits the Ca2⁺/CaMKII/CaN pathway by attenuating calcium-sensing receptor sensitivity, reducing Ca²⁺ release from the sarcoplasmic reticulum, and decreasing intracellular Ca²⁺ to prevent calcium overload (Lu et al., 2018). Similarly, Yin et al. hypothesized that AS-IV reduces calcium overload by inhibiting galanin receptor activity, enhances ERK1/2 phosphorylation, and mitigates cardiomyocyte apoptosis induced by I/R (Yin et al., 2019). These findings suggest AS-IV’s critical role in regulating calcium channel activity and maintaining intra- and extracellular calcium balance.

Beyond calcium homeostasis, AS-IV also modulates dysfunctions in other ion channels. For instance, AS-IV prolongs action potential duration in guinea pig ventricular myocytes by inhibiting delayed rectifier K⁺ channels and enhancing inward rectifier K⁺ channels (Zhao et al., 2013). Studies further indicate that in advanced I/R stages, AS-IV activates mitochondrial ATP-sensitive K⁺ channels, leading to depolarization, reduced mitochondrial Ca²⁺ uptake, and decreased mitochondrial calcium overload (Guan et al., 2015).

As age progresses, the risk of cardiovascular diseases, including atrial and ventricular arrhythmias, rises significantly. Clinical studies have established a robust correlation between biological aging and AF incidence. In a study of 5,600 participants with an average age of 65.5 years, epigenetic clocks (e.g., DNAm GrimAge and DNAm PhenoAge) were utilized to assess biological age. Findings indicated that each 5-year increase in epigenetic age was associated with a 19% increase in AF risk, while acceleration of DNAm PhenoAge was linked to a 15% rise in AF risk (Roberts et al., 2021). The aging process leads to reduced T-tubule density in cardiomyocytes, potentially facilitating post-depolarization phenomena, reentry events, and alternans, thereby establishing an electrophysiological basis for arrhythmia (Setterberg et al., 2021). Although the mechanisms underlying arrhythmia in older adults remain incompletely understood, cardiac structural remodeling is a recognized contributing factor (Kane et al., 2021). In aged rabbit models, senescent cardiac fibroblasts couple with cardiomyocytes, resulting in prolonged action potential duration (APD), conduction block, and an increased arrhythmia risk (Baggett et al., 2023). Furthermore, telomere shortening during aging is closely associated with atrial remodeling linked to AF. In a cohort of 155 patients with paroxysmal AF, with a mean age of 56.8 years, individuals with significant reductions in leukocyte telomere length exhibited a higher recurrence rate of AF (HR 2.68, 95% CI 1.50–4.79, P = 0.001), along with more pronounced left atrial enlargement, indicating severe atrial remodeling (Pan et al., 2019).

Research by Tahhan et al. demonstrated that an increase in redox potential (elevation of EhGSH) is significantly associated with both the prevalence and incidence of AF. Specifically, a 10% rise in EhGSH corresponded to a 30% increased likelihood of developing AF and a 40% rise in episode occurrence risk, highlighting the critical role of oxidative stress in AF pathogenesis (Samman Tahhan et al., 2017). Oxidative stress is recognized as a pivotal aging mechanism. With advancing age, mitochondrial function deteriorates, characterized by increased ROS production, accumulation of mitochondrial DNA (mtDNA) mutations, altered mitochondrial dynamics, a decline in the mitochondrial unfolded protein response (UPRmt), and reduced respiratory chain activity (Bao et al., 2023). Recent studies indicate that AS-IV effectively mitigates high-glucose-induced cellular senescence by promoting mitochondrial autophagy, maintaining mitochondrial dynamic homeostasis, and enhancing energy metabolism (Jun-li et al., 2023; Sun et al., 2023) Additionally, AS-IV reduces ROS overproduction and mitochondrial dysfunction induced by angiotensin II (Ang II), thereby inhibiting vascular smooth muscle cell senescence (Lu Y. et al., 2015).

Inflammatory responses also play a key role in cellular senescence. Interleukin-6 (IL-6) regulation is considered to be independent of the aging-related gene P53 and instead is modulated directly by the DNA damage response (DDR), influencing the IL-6 signaling complex expression on cell surfaces (Rodier et al., 2009). Similarly, interleukin-1 (IL-1) protein is upregulated during cellular senescence, enhancing NF-κB-mediated inflammatory cascade activation (Lau et al., 2019). In a study involving 72 patients with chronic heart failure (CHF), Astragalus injection significantly reduced inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and IL-6, in elderly CHF patients (Zhang et al., 2005). Experimental evidence indicates that AS-IV downregulates advanced glycation end product (AGE) expression in hippocampal tissue in aging model rats, thereby inhibiting AGE-RAGE protein interactions on neurons and inflammatory cells, suppressing NF-κB pathway activation, and reducing inflammation-related factors such as IL-6, IL-1β, and TNF-α. This effect alleviates hippocampal neuronal inflammation and improves memory deficits in D-gal-induced aging model rats (Li W. et al., 2022).

Protein homeostasis is intimately linked with aging and longevity. Biomarkers of aging include the status of chaperone proteins, autophagy-lysosome and ubiquitin-proteasome system activities, and UPRER and UPRmt functionality (Henning and Brundel, 2017). Recent studies reveal that ERS, strongly correlated with protein homeostasis, is closely linked to arrhythmia. The relationship between the endoplasmic reticulum and mitochondria is essential in combating cellular apoptosis and stress. Studies indicate that 50 μM AS-IV significantly inhibits GSK-3β kinase activity in 2-DG-induced PC12 cells, prevents mitochondrial permeability transition pore (mPTP) opening, downregulates IRE1 and p-PERK, and thus mitigates mitochondrial damage and apoptosis under ERS (Fu et al., 2020). In diabetic nephropathy models, the AS-IV group showed significantly reduced expressions of GRP78 and IRE-1α, key ERS regulators, resulting in suppression of NF-κB/NLRP3 pathway activation, downregulation of NF-κB p65 and IL-1β, and subsequent inflammation and podocyte apoptosis mitigation in diabetic nephropathy rats (Sun et al., 2024). Similarly, Zhao et al. showed that AS-IV inhibits IRE-1α/TXNIP/NLRP3 signaling, reduces ROS production, and downregulates caspase-1 and IL-1β, alleviating oxidative stress and inflammation associated with ERS, and reducing endothelial cell apoptosis. AS-IV also activates AMP-activated protein kinase (AMPK), promotes TXNIP degradation, and inhibits TXNIP activity, protecting endothelial cells from TXNIP/NLRP3 inflammasome-induced damage (Zhao Y. et al., 2015). Although current research primarily focuses on non-cardiac diseases, these findings highlight AS-IV’s potential in modulating ERS in cardiac arrhythmias.

Cellular senescence is dynamic, often compromising normal tissue functionality by continuously secreting pro-inflammatory cytokines, chemokines, growth factors, and matrix metalloproteinases—collectively termed senescence-associated secretory phenotype (SASP) factors. SASP factors mediate chronic inflammation, activate cardiac fibroblasts, and exacerbate cellular senescence and tissue damage (Huang et al., 2022; Mehdizadeh et al., 2022). Aging cardiomyocytes significantly increase SASP factor expression, including CCN1, ILs (1α, 1β, and 6), TNF-α, MCP-1, TGF-β, and GDF15, which are closely associated with age-related cardiovascular dysfunction (Mehdizadeh et al., 2022). For instance, senescent M1 macrophages within atherosclerotic plaques release SASPs, increasing oxidative stress levels within plaques, leading to instability, rupture, and a heightened risk of AF (Vellasamy et al., 2022). Recent studies demonstrate that AS-IV mitigates isoproterenol (ISO)-induced myocardial injury and fibrosis by suppressing SASP release and modulating the p53 signaling pathway (Shi et al., 2024). AS-IV also supports the function of key ion channels (e.g., HCN4) in the heart by enhancing anti-aging protein Klotho expression, reducing arrhythmia likelihood (Qiu et al., 2016).

Hyperglycemia is recognized as an independent risk factor for the onset of AF. A study of 8,943 patients with impaired glucose tolerance demonstrated that for every 1 mmol/L increase in fasting blood glucose, the risk of AF increased by 33%, indicating that elevated blood glucose levels may contribute to AF even before diabetes is diagnosed (Latini et al., 2013). Compared to the general population, patients with diabetes and those with stage 5 CKD show a threefold higher risk of developing AF (Seyed Ahmadi et al., 2020). Additionally, the presence of diabetes exacerbates the bleeding risk in patients with AF (Chan et al., 2020). Diabetes-induced oxidative stress and inflammation are crucial factors in the pathogenesis of AF. Hyperglycemia impairs mitochondrial function, leading to excessive production of ROS (Yuan et al., 2020), which directly damages cardiomyocytes, causing atrial fibrosis and abnormal electrical activities (Liang et al., 2018). ROS further contributes to myocardial structural and electrical remodeling by promoting the release of inflammatory factors such as TNF-α and IL-6. Chronic inflammation, in turn, enhances the expression of pro-fibrotic factors via the activation of pathways like NF-κB, damaging atrial intercellular junction proteins (e.g., Cx40 and Cx43) and affecting electrical signal transmission in the myocardium (Karam et al., 2017). The combined effects of oxidative stress and inflammation facilitate atrial fibrosis and electrical remodeling in diabetic patients, thereby increasing the risk of AF.

AS-IV shows significant potential in glycemic control. In a randomized controlled trial targeting type 2 diabetes mellitus patients with chronic kidney disease, Astragalus administration significantly reduced fasting blood glucose and HbA1c levels and improved insulin resistance (Chan et al., 2024). Liang et al. reported that Astragalus combined with insulin markedly increased SOD levels, decreased MDA content, reduced oxygen free radical generation, and enhanced antioxidant activity in pancreatic islet cells, thus effectively lowering blood glucose levels in patients with gestational diabetes (Liang et al., 2009). Xu et al. found that AS-IV improved hyperglycemia, insulin resistance, and glucose tolerance in diet-induced and genetically obese mice by elevating circulating levels of adiponectin (Xu et al., 2009).

AS-IV has demonstrated efficacy in alleviating diabetes and its complications through antioxidant, anti-inflammatory, anti-fibrotic, and anti-ferroptotic mechanisms. A meta-analysis on Astragalus and its extracts in stage III-IV diabetic nephropathy revealed that Astragalus inhibited early macrophage-induced nitric oxide synthase activity triggered by lipopolysaccharide, reduced NO and TNF-α production, and decreased apoptosis in renal tubular epithelial cells (Lai et al., 2013; Wang et al., 2016; Liao et al., 2017). Furthermore, Su et al. showed that AS-IV activates the PI3K/AKT/Nrf2/ARE signaling pathway, enhancing Nrf2 expression and nuclear translocation, binding to the ARE upstream, and increasing downstream antioxidant protein expression (e.g., Ho-1, Gpx-1, Gclc, and Gclm), which mitigates oxidative stress in glomerular mesangial cells (GMCs) induced by high glucose. This study further revealed that AS-IV can limit NF-κB nuclear translocation in high-glucose-stimulated GMCs by upregulating Nrf2 and reducing ROS generation, subsequently downregulating inflammatory markers like MCP-1, TNFα, IL-1β, IL-6, and fibrosis markers Fn and Col IV downstream of NF-κB, thereby ameliorating GMC inflammation and fibrotic damage under high glucose (Su et al., 2023). Deng et al. demonstrated that AS-IV reduces blood glucose levels and increases serum insulin in juvenile mice with diabetic ketoacidosis (DKA). AS-IV also enhances catalase and glutathione peroxidase secretion in pancreatic tissue, degrading H2O2, preventing ROS interactions, and thereby increasing SOD activity and reducing MDA levels, which mitigates oxidative stress damage in DKA pancreatic tissue through the activation of the JNK/Nrf2 signaling pathway. Notably, when JNK and Nrf2 expression is silenced, AS-IV’s protective effects on pancreatic oxidative stress in DKA are diminished, though AS-IV still improves glucose and insulin levels in these juvenile mice (Deng, 2020). Additionally, AS-IV mitigates myocardial dysfunction in diabetic cardiomyopathy rats by downregulating CD36-mediated ferroptosis (Li et al., 2023). Tang et al. demonstrated that AS-IV alleviates ferroptosis in retinal pigment epithelial cells under high glucose by modulating the miR-138–5p/Sirt1/Nrf2 signaling pathway (Tang et al., 2022).

These findings suggest that AS-IV may improve metabolic status, reduce oxidative stress and inflammation, and potentially aid in the prevention or delay of diabetic complications such as AF.

Obesity is not only a well-established cardiovascular risk factor but also significantly increases the risk of sudden cardiac death and AF. Research has shown that the recurrence rate of AF is 20% in patients who undergo bariatric surgery, compared to as high as 55% in morbidly obese individuals who do not undergo such interventions (Donnellan et al., 2019). In the renowned Framingham Heart Study, a detailed analysis of clinical data from 5,204 participants revealed that the risk of developing new-onset AF among obese individuals was twice as high as that in individuals of normal weight. Furthermore, for each unit increase in body mass index, the risk of AF rose by 7% in men and 9% in women. Left atrial enlargement resulting from obesity was identified as the primary mediator of AF, underscoring a significant correlation between obesity and atrial structural remodeling (Parish, 2005). Obesity contributes to the creation of substrates conducive to arrhythmia (Pathak et al., 2015), facilitating the onset and progression of AF. These substrates include lipid metabolism disorders, elevated blood pressure, chronic inflammation, cardiac structural remodeling, and electrophysiological abnormalities (Lavie et al., 2017; Middeldorp et al., 2023). Therefore, controlling obesity is crucial for mitigating the risk of arrhythmias.

Previous studies have demonstrated that AS-IV is effective in managing obesity and reducing body weight. A study involving 84 patients with gestational diabetes showed that, compared to insulin therapy alone, the combination of insulin and astragalus significantly reduced levels of total cholesterol, triglycerides, and low-density lipoproteins (Liang et al., 2009). AS-IV notably reduced body weight in aged mice, decreased white adipose tissue, and lowered the liver-to-body weight ratio. It also significantly decreased triglyceride (TG) levels in both serum and liver, enhanced fatty acid mobilization in white adipose tissue, promoted mitochondrial fatty acid oxidation, and facilitated mitochondrial biogenesis in the liver (Luo Z. et al., 2021).

AS-IV modulates the Akt/PDE3B pathway to inhibit cAMP accumulation, thereby suppressing lipid catabolism, which is beneficial for limiting liver lipid deposition and reducing excessive hepatic glucose production (Du et al., 2018). Additionally, AS-IV activates AMPK to alleviate ERS and lipid accumulation induced by free fatty acids in hepatocytes, showing potential therapeutic efficacy in hepatic steatosis (Zhou et al., 2017). Liang et al. found that AS-IV significantly reduced levels of AST, ALT, and TG in the serum of non-alcoholic fatty liver disease mice (Liang et al., 2021). Further studies suggested that the mechanism might involve the suppression of the TLR4/MyD88/NF-κB signaling pathway by AS-IV, which downregulates the expression of downstream inflammatory cytokines such as TNF-α, IL-6, and IL-8, thereby alleviating the inflammatory response induced by liver steatosis (Liu et al., 2020).

AS-IV also regulates blood glucose and lipid metabolism through modulation of the gut microbiota. Studies have shown that AS-IV downregulates the expression of intestinal fibroblast growth factor 15, activates the liver farnesoid X receptor (FXR) signaling pathway, upregulates glucagon-like peptide-1, and reduces ceramide production, thereby modulating lipid synthesis processes that regulate cholesterol transport and optimize lipid metabolism in the liver (Zhai et al., 2022). Moreover, AS-IV has been shown to mitigate obesity-related hypertension by repressing inflammatory responses and enhancing leptin resistance, likely through upregulation of α7nAchR levels and inhibition of IKKβ/NF-κB signaling in the hypothalamus and adipose tissue (Jiang et al., 2018).

Given the strong link between obesity and arrhythmia, the aforementioned studies suggest that astragaloside may reduce the likelihood of arrhythmia by regulating fat metabolism. While a considerable body of basic research has revealed the potential beneficial effects of astragalus on obesity-related arrhythmias, clinical evidence directly demonstrating its efficacy in obesity management remains limited. Therefore, further clinical trials are essential to validate the precise therapeutic potential of astragaloside in obesity management, which will provide stronger support for its use in patients with arrhythmia.