Mechanism of tonifying-kidney Chinese herbal medicine in the treatment of chronic heart failure

Abstract

According to traditional Chinese medicine (TCM), chronic heart failure has the basic pathological characteristics of "heart-kidney yang deficiency." Chronic heart failure with heart- and kidney-Yang deficiency has good overlap with New York Heart Association (NYHA) classes III and IV. Traditional Chinese medicine classical prescriptions for the treatment of chronic heart failure often take "warming and tonifying kidney-Yang" as the core, supplemented by herbal compositions with functions of "promoting blood circulation and dispersing blood stasis." Nowadays, there are still many classical and folk prescriptions for chronic heart failure treatment, such as Zhenwu decoction, Bushen Huoxue decoction, Shenfu decoction, Sini decoction, as well as Qili Qiangxin capsule. This review focuses on classical formulations and their active constituents that play a key role in preventing chronic heart failure by suppressing inflammation and modulating immune and neurohumoral factors. In addition, given that mitochondrial metabolic reprogramming has intimate relation with inflammation, cardiac hypertrophy, and fibrosis, the regulatory role of classical prescriptions and their active components in metabolic reprogramming, including glycolysis and lipid β-oxidation, is also presented. Although the exact mechanism is unknown, the classical TCM prescriptions still have good clinical effects in treating chronic heart failure. This review will provide a modern pharmacological explanation for its mechanism and offer evidence for clinical medication by combining TCM syndrome differentiation with chronic heart failure clinical stages.

Keywords: chronic heart failure; classical prescription; energy metabolism; inflammation; neurohumoral factors.

Figure 1

The modern medical understanding that kidney-Yang deficiency promotes the development of chronic heart failure. Kidney-Yang deficiency leads to metabolic disturbances, endocrine disorders, immune function imbalance, and low-grade chronic inflammation, which further contributes to vascular dysfunction, hypertension, chronic kidney disease, and cardiac tissue and functional imbalance, and eventually guides to chronic heart failure.

Figure 2

Inhibitory effect of classic formulations and their active ingredients on norepinephrine secretion and neural excitability in the hypothalamus. Circulating pro-inflammatory factors enhance sympathetic excitability and the risk of heart failure. SFO's perception of circulating proinflammatory factors leads to increased secretion of norepinephrine in PVN neurotransmitters and promotes sympathetic excitability, resulting in microvascular contraction, renal fluid retention and increased renin release, raising the level of angiotensin II and aldosterone in blood, elevating heart rate and arrhythmia, and causing left ventricular hypertrophy.

Figure 3

Improvement of heart failure by classic prescription via HPA axis. Kidney Yang deficiency is linked to heart failure via the hypothalamic-pituitary-adrenal axis. Under the condition of kidney-Yang deficiency driven by factors such as advanced age, the secretion of CRH secreted by PVN decreases, the activation of the hypothalamic-pituitary-adrenal axis is inhibited, the expression of 11β-HSD2 drops while the expression of mineralocorticoid receptor (MR) rises, cardiac hypertrophy and fibrosis, and functional events increased.

Figure 4

Inhibitory effect of the active ingredients of the classic formulas of invigorating kidney on the key enzymes related to glycolysis in the mitochondrial hexose pathway caused by heart failure. The active ingredients in the classic formulas have inhibitory effects on the enzymatic activity or expression of HK2, PKM2, LDHA, and PDK, respectively.

Figure 5

Transcriptional regulation of gene expression related to metabolic reprogramming by active ingredients in classical formulas. Heart failure and inflammation trigger the activity of transcription factors c-Myc, mTOR, STAT3, and HIF-1 to change the expression and activity of enzymes related to glycolysis, fatty acid β-oxidation, and glutaminolysis.

Figure 6

Active ingredients in the classic formulas activate the expression or activity of CPT1 and improve fatty acid β-oxidation with or without the AMPK pathway. CPT1 is a key channel for long-chain fatty acids across the mitochondrial outer membrane, and its activity or expression affects the β-oxidation of fatty acids.

Figure 7

Inhibitory effect of active ingredients in classical recipes on hnRNP A1-mediated alternative splicing of PKM2, either directly or via activation of Sirt1. The heterogeneous nuclear ribonucleoprotein, which packs newly produced precursor mRNA, is acetylated and stabilized under conditions of heart failure and inflammation, and then selectively splices PKM2 mRNA to promote glycolysis.