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<div><p>Background</p><p><i>Ginseng Radix et Rhizoma</i> (GS) is frequently used as an adjuvant therapy for patients with heart failure (HF). Metoprolol is widely used in patients with HF. However, there is no report on the combined effects of GS and metoprolol in patients with HF.</p><p>Objective</p><p>This study investigated the combined effects of GS and metoprolol in male C57BL/6J mice with HF and the underlying mechanisms.</p><p>Materials and methods</p><p>We utilized a mouse myocardial HF model to measure the serum levels of creatine kinase (CK) and creatine kinase-MB form (CK-MB) using an automated biochemical analyzer. Lactate dehydrogenase (LDH) and cardiac troponin (cTnT) levels were determined using enzyme-linked immunosorbent assays. Autophagy of myocardial cells was evaluated using transmission electron microscopy, and changes in signal pathway proteins related to autophagy were analyzed by Western blotting.</p><p>Results</p><p>GS combined with metoprolol improved heart function, reduced heart damage, and decreased serum levels of CK, CK-MB, LDH, and cTnT. The combination of GS and metoprolol decreased autophagy in myocardial cells by reducing the levels of autophagy-related proteins (LC3, p62, Beclin1, and Atg5) and increasing the ratios of p-PI3K/PI3K, p-Akt/Akt, and p-mTOR/mTOR.</p><p>Conclusion</p><p>GS enhanced the anti-heart failure effect of metoprolol. Its mechanism of action might be related to the inhibition of autophagy mediated by the activation of the PI3K/Akt/mTOR pathway.</p></div>