Proteomic Evaluation of the Comorbidity-Inflammation Paradigm in Heart Failure With Preserved Ejection Fraction: Results From the PROMIS-HFpEF Study.
Proteomic Evaluation of the Comorbidity-Inflammation Paradigm in Heart Failure With Preserved Ejection Fraction: Results From the PROMIS-HFpEF Study.
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DOI：
10.1161/circulationaha.120.045810
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发表时间：
2020-11-24
期刊：
影响因子：
37.8
通讯作者：
Shah SJ
中科院分区：
文献类型：
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作者：
Sanders-van Wijk S;Tromp J;Beussink-Nelson L;Hage C;Svedlund S;Saraste A;Swat SA;Sanchez C;Njoroge J;Tan RS;Fermer ML;Gan LM;Lund LH;Lam CSP;Shah SJ
已假设全身促炎状态介导射血分数保留性心力衰竭（HFpEF）中合并症与心脏结构/功能异常之间的相关性。我们进行了蛋白质组学分析来研究这种模式。在多中心PROMIS-HFpEF研究的228例HFpEF患者中，通过多重免疫测定（Olink）定量了248种独特的循环蛋白，并用于概括全身炎症。在演绎方法中，我们进行了主成分（PC）分析，总结了47种先验已知与炎症有关的蛋白质。在一种归纳方法中，我们对所有248种蛋白质进行了无偏加权共表达网络分析，以确定过度代表炎症通路的蛋白质簇。我们将合并症负担定义为8种常见HFpEF合并症的总和。我们使用多变量线性回归和统计中介分析来确定炎症是否以及在多大程度上介导HFpEF患者合并症负荷与心脏结构/功能异常的相关性。我们还在117例HFpEF病例和30例无HF的合并症对照的独立队列中外部验证了我们的研究结果。合并症负荷与心脏结构/功能异常和PC/炎症蛋白簇相关。全身性炎症还与二尖瓣E流速、E/e'比值和三尖瓣返流（TR）流速增加以及右心室功能（三尖瓣环平面收缩期偏移[TAPSE]和右心室功能）恶化相关。[RV]自由壁应变）。炎症介导了合并症负荷与二尖瓣E流速（比例介导19-35%）、E/e'比值（18-29%）、TR流速（27-41%）和三尖瓣环平面收缩期偏移（13%）之间的相关性（全部P<0.05），但与RV游离壁应变无关。TNF-R1、UPAR、IGFBP-7和GDF-15是介导合并症负荷与超声心动图参数之间关系的主要蛋白质。在验证队列中，与对照相比，HFpEF病例中的炎症上调，并且在PROMIS-HFpEF中鉴定的最突出的炎症蛋白簇也存在于验证队列中的HFpEF病例（但不是对照）中。参与炎症的蛋白质在2个独立队列的HFpEF中形成保守网络，并可能介导合并症负荷与血流动力学恶化和RV功能障碍的超声心动图指标之间的相关性。这些发现支持HFpEF中的共病-炎症范例。
A systemic pro-inflammatory state has been hypothesized to mediate the association between comorbidities and abnormal cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). We conducted a proteomic analysis to investigate this paradigm. In 228 HFpEF patients from the multicenter PROMIS-HFpEF study, 248 unique circulating proteins were quantified by a multiplex immunoassay (Olink) and used to recapitulate systemic inflammation. In a deductive approach, we performed principal component (PC) analysis to summarize 47 proteins known a priori to be involved in inflammation. In an inductive approach, we performed unbiased weighted co-expression network analyses of all 248 proteins to identify clusters of proteins that overrepresented inflammatory pathways. We defined comorbidity burden as the sum of 8 common HFpEF comorbidities. We used multivariable linear regression and statistical mediation analyses to determine whether and to what extent inflammation mediates the association of comorbidity burden with abnormal cardiac structure/function in HFpEF. We also externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without HF. Comorbidity burden was associated with abnormal cardiac structure/function and with PCs/clusters of inflammation proteins. Systemic inflammation was also associated with increased mitral E velocity, E/e’ ratio, and tricuspid regurgitation (TR) velocity; and worse right ventricular function (tricuspid annular plane systolic excursion [TAPSE] and right ventricular. [RV] free wall strain). Inflammation mediated the association between comorbidity burden and mitral E velocity (proportion mediated 19–35%), E/e’ ratio (18–29%), TR velocity (27–41%), and tricuspid annular plane systolic excursion (13%) (P<0.05 for all) but not RV free wall strain. TNF-R1, UPAR, IGFBP-7 and GDF-15 were the top individual proteins that mediated the relationship between comorbidity burden and echocardiographic parameters. In the validation cohort, inflammation was upregulated in HFpEF cases versus controls, and the most prominent inflammation protein cluster identified in PROMIS-HFpEF was also present in HFpEF cases (but not controls) in the validation cohort. Proteins involved in inflammation form a conserved network in HFpEF across 2 independent cohorts and may mediate the association between comorbidity burden and echocardiographic indicators of worse hemodynamics and RV dysfunction. These findings support the comorbidity-inflammation paradigm in HFpEF.