Leptin-Aldosterone-Neprilysin Axis Identification of Its Distinctive Role in the Pathogenesis of the Three Phenotypes of Heart Failure in People With Obesity
Leptin-Aldosterone-Neprilysin Axis Identification of Its Distinctive Role in the Pathogenesis of the Three Phenotypes of Heart Failure in People With Obesity
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DOI：
10.1161/circulationaha.117.032474
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发表时间：
2018-04-10
期刊：
影响因子：
37.8
通讯作者：
Packer, Milton
中科院分区：
文献类型：
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作者：
Packer, Milton
肥胖(尤其是内脏肥胖症)可能与三种不同的心力衰竭表型有关：射血分数降低的心力衰竭、射血分数保持不变的心力衰竭和高输出量心力衰竭。这三种表型的特征都是过度分泌醛固酮和钠滞留。此外，肥胖伴随着通过瘦素受体的信号增加，瘦素受体可以促进交感神经系统和肾素-血管紧张素系统的激活，并可以直接刺激醛固酮的分泌。肥胖和肾脏交感神经的同时作用会导致Neprilysin的过度活动，从而加强瘦素和醛固酮的有害相互作用；肥胖和心力衰竭干扰脂联素信号的额外作用会加剧钠尿肽的平衡作用的丧失。这种错综复杂的神经激素相互作用导致血浆容量扩大，以及不利的心室重构和心脏纤维化。此外，醛固酮和神经溶素的活性不仅会因肥胖而增强，而且这些机制还可以促进脂肪生成和脂肪细胞功能障碍，从而增强正反馈回路。最后，在老年肥胖女性中，心外膜脂肪组织的数量和生物学的变化进一步增强了瘦素和其他促炎症脂肪因子的释放，从而导致心脏和全身炎症、终末器官纤维化和多种并存。不管表型表达如何，瘦素-醛固酮-奈普利辛轴的激活似乎对肥胖者心力衰竭的演变和进展起到了重要作用。干扰这种独特的神经激素生态系统与现有或新的治疗药物的有害相互作用的努力可能会产生独特的临床益处。
Obesity (especially visceral adiposity) can be associated with 3 different phenotypes of heart failure: heart failure with a reduced ejection fraction, heart failure with a preserved ejection fraction, and high-output heart failure. All 3 phenotypes are characterized by an excessive secretion of aldosterone and sodium retention. In addition, obesity is accompanied by increased signaling through the leptin receptor, which can promote activation of both the sympathetic nervous system and the renin-angiotensin system and can directly stimulate the secretion of aldosterone. The deleterious interaction of leptin and aldosterone is potentiated by the simultaneous action of adiposity and the renal sympathetic nerves to cause overactivity of neprilysin; the loss of the counterbalancing effects of natriuretic peptides is exacerbated by an additional effect of both obesity and heart failure to interfere with adiponectin signaling. This intricate neurohormonal interplay leads to plasma volume expansion as well as to adverse ventricular remodeling and cardiac fibrosis. Furthermore, the activity of aldosterone and neprilysin is not only enhanced by obesity, but these mechanisms can also promote adipogenesis and adipocyte dysfunction, thereby enhancing the positive feedback loop. Last, in elderly obese women, changes in quantity and biology of epicardial adipose tissue further enhances the release of leptin and other proinflammatory adipokines, thereby leading to cardiac and systemic inflammation, end-organ fibrosis, and multiple comorbidities. Regardless of the phenotypic expression, activation of the leptin-aldosterone-neprilysin axis appears to contribute importantly to the evolution and progression of heart failure in people with obesity. Efforts to interfere with the detrimental interactions of this distinctive neurohormonal ecosystem with existing or novel therapeutic agents are likely to yield unique clinical benefits.