Qiliqiangxin: A multifaceted holistic treatment for heart failure or a pharmacological probe for the identification of cardioprotective mechanisms?

Abstract

The active ingredients in many traditional Chinese medicines are isoprene oligomers with a diterpenoid or triterpenoid structure, which exert cardiovascular effects by signaling through nutrient surplus and nutrient deprivation pathways. Qiliqiangxin (QLQX) is a commercial formulation of 11 different plant ingredients, whose active compounds include astragaloside IV, tanshione IIA, ginsenosides (Rb1, Rg1 and Re) and periplocymarin. In the QUEST Trial, QLQX reduced the combined risk of cardiovascular death or heart failure hospitalization (hazard ratio 0.78 [95% CI 0.68‐0.90]), based on 859 events in 3119 patients over a median of 18.2 months; the benefits were seen in patients taking foundational drugs except for SGLT2 inhibitors. Numerous experimental studies of QLQX in diverse cardiac injuries have yielded highly consistent findings. In marked abrupt cardiac injury, QLQX mitigated cardiac injury by upregulating nutrient surplus signaling through the PI3K/Akt/mTOR/HIF‐1α/NRF2 pathway; the benefits of QLQX were abrogated by suppression of PI3K, Akt, mTOR, HIF‐1α or NRF2. In contrast, in prolonged measured cardiac stress (as in chronic heart failure), QLQX ameliorated oxidative stress, maladaptive hypertrophy, cardiomyocyte apoptosis, and proinflammatory and profibrotic pathways, while enhancing mitochondrial health and promoting glucose and fatty acid oxidation and ATP production. These effects are achieved by an action of QLQX to upregulate nutrient deprivation signaling through SIRT1/AMPK/PGC‐1α and enhanced autophagic flux. In particular, QLQX appears to enhance the interaction of PGC‐1α with PPARα, possibly by direct binding to RXRα; silencing of SIRT1, PGC‐1α and RXRα abrogated the favorable effects of QLQX in the heart. Since PGC‐1α/RXRα is also a downstream effector of Akt/mTOR signaling, the actions of QLQX on PGC‐1α/RXRα may explain its favorable effects in both acute and chronic stress. Intriguingly, the individual ingredients in QLQX — astragaloside IV, ginsenosides, and tanshione IIA — share QLQX's effects on PGC‐1α/RXRα/PPARα signaling. QXQL also contains periplocymarin, a cardiac glycoside that inhibits Na+‐K+‐ATPase. Taken collectively, these observations support a conceptual framework for understanding the mechanism of action for QLQX in heart failure. The high likelihood of overlap in the mechanism of action of QLQX and SGLT2 inhibitors requires additional experimental studies and clinical trials.This article is protected by copyright. All rights reserved.

December 2023 at a glance: Focus on medical therapy in chronic and acute heart failure

“…In the QUEST trial, qiliqiangxin reduced the risk of cardiovascular (CV) death or HF hospitalization in patients with a background HF therapy. Packer reviewed multiple molecular pathways that may explain the benefits of qiliqiangxin highlighting similarities and differences with current treatments for HF, including sodium–glucose cotransporter 2 inhibitors (SGLT2i) 2,3 …”

“…Packer reviewed multiple molecular pathways that may explain the benefits of qiliqiangxin highlighting similarities and differences with current treatments for HF, including sodium-glucose cotransporter 2 inhibitors (SGLT2i). 2,3 Sudden cardiac death (SCD) remains an important cause of mortality in cardiomyopathies. 4 Polovina et al 5 reviewed the incidence, risk factors and management of life-threatening arrhythmias and SCD.…”