Department of Cardiovascular Disease (M.S.S., A.U.F., B.A.B., M.M.R.), Mayo Clinic, Rochester, MN.
Center for Regenerative Medicine (M.S.S.), Mayo Clinic, Rochester, MN.
Circ Heart Fail. 2020 Aug;13(8):e006414. doi: 10.1161/CIRCHEARTFAILURE.119.006414. Epub 2020 Jul 29.
Comorbidity-driven microvascular inflammation is posited as a unifying pathophysiologic mechanism for heart failure with preserved ejection fraction (HFpEF). Obesity is proinflammatory and common in HFpEF. We hypothesized that unique obesity-inflammation HFpEF phenotypes exist and are associated with differences in clinical features, fibrosis biomarkers, and functional performance.
Patients (n=301) from 3 HFpEF clinical trials were studied. Unsupervised machine learning (hierarchical clustering) with obese status and 13 inflammatory biomarkers as input variables was performed. Associations of clusters with HFpEF severity and fibrosis biomarkers (PIIINP [procollagen III N-terminal peptide], CITP [C-telopeptide for type I collagen], IGFBP7 [insulin-like growth factor-binding protein-7], and GAL-3 [galectin-3]) were assessed.
Hierarchical clustering revealed 3 phenotypes: pan-inflammatory (n=129; 64% obese), noninflammatory (n=83; 55% obese), and obese high CRP (C-reactive protein; n=89; 98% obese). The pan-inflammatory phenotype had more comorbidities and heart failure hospitalizations; higher left atrial volume, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and fibrosis biomarkers; and lower glomerular filtration rate, peak oxygen consumption, 6-minute walk distance, and active hours/day (<0.05 for all). The noninflammatory phenotype had the most favorable values for all measures. The obese high CRP phenotype resembled the noninflammatory phenotype except for isolated elevation of CRP and lower functional performance. Hierarchical cluster assignment was independent of CRP genotype combinations that alter CRP levels and more biologically plausible than other clustering approaches. Multiple traditional analytic techniques confirmed and extended the hierarchical clustering findings.
Unique obesity-inflammation phenotypes exist in HFpEF and are associated with differences in comorbidity burden, HFpEF severity, and fibrosis. These data support comorbidity-driven microvascular inflammation as a pathophysiologic mechanism for many but not all HFpEF patients.
合并症驱动的微血管炎症被认为是射血分数保留的心力衰竭（HFpEF）的统一病理生理机制。肥胖症具有炎症性，并且在 HFpEF 中很常见。我们假设存在独特的肥胖症-炎症性 HFpEF 表型，并且与临床特征、纤维化生物标志物和功能表现的差异相关。
对 3 项 HFpEF 临床试验的 301 名患者进行研究。使用肥胖状态和 13 种炎症生物标志物作为输入变量进行无监督机器学习（层次聚类）。评估聚类与 HFpEF 严重程度和纤维化生物标志物（PIIINP[III 型前胶原 N 端肽]、CITP[I 型胶原 C 端肽]、IGFBP7[胰岛素样生长因子结合蛋白-7]和 GAL-3[半乳糖凝集素-3]）的关联。
层次聚类揭示了 3 种表型：全炎症型（n=129；64%肥胖）、非炎症型（n=83；55%肥胖）和肥胖型高 CRP（C 反应蛋白；n=89；98%肥胖）。全炎症表型具有更多的合并症和心力衰竭住院治疗；更高的左心房容积、NT-proBNP（N 末端 B 型利钠肽前体）和纤维化生物标志物；以及更低的肾小球滤过率、峰值耗氧量、6 分钟步行距离和每日活跃时间（所有 P<0.05）。非炎症表型在所有指标中具有最有利的值。肥胖型高 CRP 表型除 CRP 单独升高和功能表现降低外，与非炎症表型相似。层次聚类分配独立于改变 CRP 水平的 CRP 基因型组合，并且比其他聚类方法更具有生物学意义。多种传统分析技术证实并扩展了层次聚类结果。
HFpEF 中存在独特的肥胖症-炎症表型，并且与合并症负担、HFpEF 严重程度和纤维化的差异相关。这些数据支持合并症驱动的微血管炎症作为许多但不是所有 HFpEF 患者的病理生理机制。
