From Systemic Inflammation to Myocardial Fibrosis: The Heart Failure With Preserved Ejection Fraction Paradigm Revisited.
From Systemic Inflammation to Myocardial Fibrosis: The Heart Failure With Preserved Ejection Fraction Paradigm Revisited.
复制标题
从全身炎症到心肌纤维化：重新审视保留射血分数范式的心力衰竭。
DOI：
10.1161/circresaha.121.318159
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发表时间：
2021-05-14
影响因子：
20.1
通讯作者：
Zile MR
中科院分区：
文献类型：
--
作者：
Paulus WJ;Zile MR
免疫活性细胞对心肌的浸润不仅是由于肥胖引起的代谢负荷，也是由于动脉高血压引起的血流动力学负荷。后者是由细胞外基质的成分，如基底层粘连蛋白，也与心肌细胞肌联蛋白相互作用;诱导型一氧化氮合酶在心肌细胞中的表达，因为循环促炎细胞因子。由于未折叠蛋白质应答失败，这导致降解蛋白质的心肌蓄积;通过机器学习算法定义具有不同炎症/促纤维化特征的HFpEF患者的表型组;在共病、炎症生物标志物和紊乱的心肌结构/功能与早期临床前HFpEF（HF阶段A，B）中已经明显的粘附分子内皮表达之间的介导分析中的直接耦合。根据合并症-炎症范例，合并症，尤其是代谢性合并症被认为通过从全身性炎症到心肌纤维化的一系列事件来驱动射血分数保留性心力衰竭（HFpEF）的发展和严重程度。最近，出现了新的实验和临床证据，加强了炎症/促纤维化范式的有效性。这些证据包括：这一新证据为未来的HFpEF治疗铺平了道路，如针对炎症细胞因子的生物制剂，磷酸二酯酶1抑制剂刺激蛋白泛素化，通过利钠肽-颗粒鸟苷酸环化酶-PDE 9信号传导纠正肌联蛋白僵硬，以及控制心肌纤维化的分子/细胞调节机制。
Myocardial infiltration by immunocompetent cells not only because of an obesity-induced metabolic load but also because of an arterial hypertension-induced hemodynamic load. The latter is sensed by components of the extracellular matrix like basal laminin, which also interact with cardiomyocyte titin; Expression in cardiomyocytes of inducible nitric oxide synthase because of circulating proinflammatory cytokines. This results in myocardial accumulation of degraded proteins because of a failing unfolded protein response; Definition by machine learning algorithms of phenogroups of HFpEF patients with a distinct inflammatory/profibrotic signature; Direct coupling in mediation analysis between comorbidities, inflammatory biomarkers and deranged myocardial structure/function with endothelial expression of adhesion molecules already apparent in early preclinical HFpEF (HF stage A, B). In accordance with the comorbidity-inflammation paradigm, comorbidities and especially metabolic comorbidities are presumed to drive development and severity of heart failure with preserved ejection fraction (HFpEF) through a cascade of events ranging from systemic inflammation to myocardial fibrosis. Recently, novel experimental and clinical evidence emerged, that strengthens the validity of the inflammatory/profibrotic paradigm. This evidence consists among others of: This new evidence paves the road for future HFpEF treatments such as biologicals directed against inflammatory cytokines, stimulation of protein ubiquitylation with phosphodiesterase 1 inhibitors, correction of titin stiffness through natriuretic peptide – particulate guanylyl cyclase – PDE9 signaling and molecular/cellular regulatory mechanisms that control myocardial fibrosis.