Shensong Yangxin Protects Against Metabolic Syndrome-Induced Ventricular Arrhythmias by Inhibiting Electrical Remodeling

Abstract

Shensong Yangxin (SSYX) is a traditional Chinese medicine, which has been proven to improve the clinical symptoms of arrhythmia. However, the role of SSYX in metabolic syndrome (MetS)-induced electrical remodeling remains to be fully elucidated. Here, we sought to clarify whether SSYX can alter the electrophysiological remodeling of cardiac myocytes from MetS rats by regulating transient outward potassium current ( I to ) and calcium current ( I Ca-L ). Male Wistar rats were subjected to 16 weeks of high-carbohydrate, high-fat to produce a MetS model group. SSYX (0.4 g/kg) was administrated by daily gavage 8 weeks following high-carbohydrate, high-fat for 8 weeks. In vivo electrophysiological study was performed to evaluated ventricular arrhythmias (VA) vulnerability and electrophysiological properties. The potential electrical mechanisms were estimated by whole-cell patch-clamp and molecular analysis. The H9C2 cells were used to verify the protective role of SSYX in vitro . After 16-week high-carbohydrate, high-fat feeding, MetS model rats showed increased body weight (BW), blood pressure (BP), blood sugar (BS), heart rate (HR) and heart weights to tibia length (HW/TL) ratio. Furthermore, MetS rats depicted increased VA inducibility, shortened effective refractory period (ERP) and prolonged action potential duration (APD). Lower I Ca-L and I to current densities were observed in MetS rats than CTL rats. Additionally, MetS rats exhibited significantly increased cardiac fibrosis, decreased Cx43 expression and protein levels of Cav1.2, Kv4.2, Kv4.3 than CTL group. As expected, these MetS-induced effects above were reversed when SSYX was administrated. Mechanistically, SSYX administrated significantly down-regulated the TLR4/MyD88/CaMKII signaling pathway both in vivo and in vitro . Collectively, our data indicated that the electrical remodeling induced by MetS contributed to the increased VA susceptibility. SSYX protects against MetS-induced VA by inhibiting electrical remodeling through TLR4/MyD88/CaMKII signaling pathway.

Integrating Evidence of the Traditional Chinese Medicine Collateral Disease Theory in Prevention and Treatment of Cardiovascular Continuum

“…Regarding these overlapped key nodes of the cardiovascular continuum, there are TCM set prescriptions based on collateral disease that could offer intervention targets at various continuum stages ( Figure 1 ). For example, Jinlida granules (JLDG) for metabolic syndrome, Tongxinluo (TXL) for atherosclerotic plaque and myocardial protection, Shensongyangxin (SSYX) capsules for anti-arrhythmias via metabolic reconstruction, and Qiliqiangxin (QLQX) capsules for cardiac remodeling and heart failure have been recognized under the guidance of translational medicine ( Table 1 ) ( Bai et al, 2013 ; Wang et al, 2014 ; Zaki et al, 2014 ; Luan et al, 2015 ; Wang et al, 2015 ; Zhang et al, 2016 ; Fan et al, 2017 ; Shen et al, 2017 ; Zhao et al, 2017 ; Chen H. et al, 2018 ; Chen Y. et al, 2018 ; Gao et al, 2018 ; Wang et al, 2018 ; Zhang et al, 2018 ; Lyu et al, 2019 ; Tung et al, 2019 ; Zhou et al, 2019 ; Cheng W. et al, 2020 ; Li et al, 2020 ; Yang et al, 2020 ; Zhao et al, 2020 ; Jiang et al, 2021 ; Hao et al, 2022 ). These set prescriptions have been approved for by the Chinese National Medical Products Administration (NMPA), and broadly used in clinical practice in the Chinese community.…”

“…Another study showed that SSYX reduces the occurrence of AF after myocardial infarction by inhibiting atrial fibrosis ( Ma et al, 2018 ). At the same time, SSYX has shown to be a multichannel blocker with measurable modulation effects on various ion channels, such as L-type calcium channel and transient outward potassium (Ito), resulting in an overall prolongation of the action potential ( Yang et al, 2020 ; Zhao et al, 2020 ). SSYX could inhibit IK1 and Ito currents by prolonging the duration of action potentials, reversing calcium overload, and inhibiting the occurrence of ventricular arrhythmias after ischemia ( Zhao et al, 2016 ).…”

“…SSYX could inhibit IK1 and Ito currents by prolonging the duration of action potentials, reversing calcium overload, and inhibiting the occurrence of ventricular arrhythmias after ischemia ( Zhao et al, 2016 ). In a metabolic aspect, animal research showed that SSYX can reverse and alleviate the metabolic and arrhythmic pathological changes such as impaired glucose tolerance, enlarged atria, atrial fibrosis, atrial inflammation, and oxidative stress; shortened effective refractory period; and prolonged action potential duration induced by metabolic syndrome ( Zaki et al, 2014 ; Chen Y. et al, 2018 ; Yang et al, 2020 ).…”

Therapeutic Effects of Traditional Chinese Medicine on Cardiovascular Diseases: the Central Role of Calcium Signaling

“…For example, hypoxia and oxidative stress mediate Ca 2+ overload in myocardial cells and generate heart rhythm irregularities and other myocardial dysfunctions (Guan et al, 2015). Several studies have evaluated and explored the therapeutic effects of common Chinese medicines and their active ingredients on arrhythmia through modulating cardiac calcium handling (Liu et al, 2017a;Yang et al, 2020a;Tian et al, 2018) (Table 2). The antiarrhythmic effect of matrine in Sophora tonkinensis was revealed in a rat arrhythmia model induced by coronary artery ligation.…”

Shensong Yangxin Capsule Reduces the Susceptibility of Arrhythmia in db/db Mice via Inhibiting the Inflammatory Response Induced by Endothelium Dysfunction

“…Shensong Yangxin (SSYX) capsules are an antiarrhythmic Chinese patent medicine that can improve microcirculation, protect endothelial cells, and reverse myocardial structural remodeling, electrical remodeling, and neural remodeling after myocardial infarction. [18][19][20][21][22][23] SSYX has been widely used to treat various arrhythmias by regulating multiple ion and non-ion channels. [24][25][26] However, whether SSYX can reduce arrhythmia susceptibility in patients with diabetes has not been studied.…”