基于“亢害承制”理论探讨慢性心力衰竭铁死亡的发生机制

Mechanism of ferroptosis in chronic heart failure based on theory of"harmful hyperactivity and responding inhibition"

慢性心力衰竭是多种病因导致的心脏疾病终末阶段,心肌细胞损伤是导致心功能恶化的关键。铁死亡以铁过载、脂质过氧化物等过度积累为特征,是一种铁依赖性的程序性死亡方式。研究表明,抑制铁死亡可以对心肌细胞产生保护作用。“亢害承制”理论是经后世医家演变用于阐释人体五行生克制化、病理失衡及指导用药的重要法则。人与天地相参,亦需依赖承制规律维持五脏调和、内腑通利的稳态。慢性心力衰竭铁死亡的发生机制高度契合“承者失制,亢者为害”的过程。心气亏虚、承制不及,无力维持心肌细胞氧化还原系统平衡,为铁死亡的始动因素。五脏受累,津血失布,痰浊、血瘀、水饮留滞经脉,表现为铁及脂质过氧化物蓄积,是铁死亡的加重因素。二者交互影响,反复叠加,呈螺旋式进展,加剧心力衰竭病情。基于铁死亡的中医病机,笔者试以“承而制之,平其所亢”为治疗总则,提出慢性心力衰竭分期论治的总纲。早期以“益气养,兼调五脏,承而制之”为主,中期以“活血化痰,祛邪化浊,平其所亢”为要,晚期以“温阳益气,活血利水,承制平亢”并重。遵守病机特点运用中药干预,可以降低铁蓄积,促进脂质过氧化物的清除,从而抑制铁死亡,改善心功能。

Chronic heart failure is the end stage of heart diseases caused by multiple causes.Myocardial cell injury is the key cause of cardiac function deterioration.Ferroptosis,an iron-dependent programmed death mode,is characterized by iron overload and excessive accumulation of lipid peroxides.Studies have demonstrated that inhibiting ferroptosis has a protective effect on myocardial cells.The theory of"harmful hyperactivity and responding inhibition"is an important rule developed by physicians to explain the generation and restriction of the five elements and the pathological imbalance of the human body,and can guide medication.Correlating with the nature,humans need to rely on the law of responding inhibition to maintain the harmony of five Zang-organs and the steady state of Fu-organs.The pathogenesis of ferroptosis in chronic heart failure highly coincides with the process of failing to"inhibition and hyperactivity becoming harmful".The initial factor of ferroptosis is the deficiency of heart Qi,which results in the inability to maintain the balance of cardiomyocyte redox system.The involvement of the five Zang-organs leads to the loss of distribution of body fluid and blood.As a result,the phlegm turbidity,blood stasis,and water retention in the meridians occur,which are manifested as the accumulation of iron and lipid peroxides,which is the aggravating factor of ferroptosis.The two factors interact with each other,leading to the spiral development and thus aggravating heart failure.According to the traditional Chinese medicine(TCM)pathogenesis of ferroptosis,the authors try to treat the chronic heart failure by stages in accordance with the general principle of restraining excess and alleviating hyperactivity.The early-stage treatment should"nourish heart Qi,regulate the five Zang-organs,so as to restrain excess".The middle-stage treatment should"active blood,resolve phlegm,dispel pathogen,and eliminate turbidity",so as to alleviate hyperactivity.The late-stage treatment should"warm Yang,replenish Qi,active blood,and excrete water".Following the characteristics of pathogenesis,the TCM intervention can reduce iron accumulation and promote the clearance of lipid peroxide,thus inhibiting ferroptosis and improving cardiac function.