Gan Sushrima, Azzo Joe David, Zhao Lei, Pourmussa Bianca, Dib Marie Joe, Salman Oday, Erten Ozgun, Ebert Christina, Richards A Mark, Javaheri Ali, Mann Douglas L, Rietzschel Ernst, Zamani Payman, van Empel Vanessa, Cappola Thomas P, Chirinos Julio A
Hospital of the University of Pennsylvania, Philadelphia (S.G., J.D.A., B.P., M.J.D., O.S., O.E., P.Z., T.P.C., J.A.C.).
Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (S.G., J.D.A., B.P., M.J.D., O.S., O.E., P.Z., T.P.C., J.A.C.).
Circ Heart Fail. 2025 Feb;18(2):e011728. doi: 10.1161/CIRCHEARTFAILURE.124.011728. Epub 2025 Jan 20.
Iron deficiency (ID) is currently defined as a serum ferritin level <100 or 100 to 299 ng/mL with transferrin saturation (TSAT) <20%. Serum ferritin and TSAT are currently used to define absolute and functional ID. However, individual markers of iron metabolism may be more informative than current arbitrary definitions of ID.
We assessed prognostic associations of ferritin, serum iron, and TSAT among 2050 participants with heart failure (HF) with reduced/mid-range (n=1821) or preserved (n=229) left ventricular ejection fraction enrolled in the PHFS (Penn HF Study), a prospective cohort study. We measured 4928 plasma proteins using an aptamer-based assay (SOMAScanv4) and assessed prognostic and proteomic associations of markers of iron metabolism.
Ferritin concentrations were not associated with outcomes, whereas low TSAT and serum iron were associated with the risk of all-cause death (TSAT: standardized hazard ratio, 0.84 [95% CI, 0.76-0.93]; =0.001; serum iron: standardized hazard ratio, 0.87 [95% CI, 0.79-0.96]; =0.007). Similarly, TSAT was associated with the risk of death or HF-related admission (standardized hazard ratio, 0.89 [95% CI, 0.83-0.95]; =0.0006). Significant interactions between TSAT and HF with preserved ejection fraction status were found such that TSAT was more strongly associated with the risk of death and death or HF-related admission in HF with preserved ejection fraction. We identified 359 proteins associated with TSAT, including TFRC (transferrin receptor protein; β, -0.455; <0.0001) and CRP (C-reactive protein; β, -0.355; <0.0001). Pathway analyses demonstrated associations with lipid metabolism, complement activation, and inflammation. In contrast to the robust associations between TSAT and outcomes, ID and absolute ID defined by current criteria were not associated with death or death or HF-related admission. TSAT was associated with outcomes regardless of the presence of functional versus absolute ID.
Low TSAT, but not ferritin concentrations, is significantly associated with adverse outcomes in HF. Low TSAT is more strongly associated with outcomes in HF with preserved ejection fraction. Pathways related to inflammation and lipid metabolism are associated with low TSAT in HF.
缺铁（ID）目前被定义为血清铁蛋白水平<100或100至299 ng/mL且转铁蛋白饱和度（TSAT）<20%。血清铁蛋白和TSAT目前用于定义绝对缺铁和功能性缺铁。然而，铁代谢的个体标志物可能比目前任意定义的缺铁更具信息量。
我们在参加前瞻性队列研究PHFS（宾夕法尼亚州心力衰竭研究）的2050例左心室射血分数降低/中等范围（n = 1821）或保留（n = 229）的心力衰竭（HF）参与者中评估了铁蛋白、血清铁和TSAT的预后关联。我们使用基于适体的检测方法（SOMAScan v4）测量了4928种血浆蛋白，并评估了铁代谢标志物的预后和蛋白质组学关联。
铁蛋白浓度与预后无关，而低TSAT和血清铁与全因死亡风险相关（TSAT：标准化风险比，0.84 [95% CI，0.76 - 0.93]；P = 0.001；血清铁：标准化风险比，0.87 [95% CI，0.79 - 0.96]；P = 0.007）。同样，TSAT与死亡或HF相关住院风险相关（标准化风险比，0.89 [95% CI，0.83 - 0.95]；P = 0.0006）。发现TSAT与射血分数保留的HF状态之间存在显著相互作用，使得TSAT在射血分数保留的HF中与死亡以及死亡或HF相关住院风险的关联更强。我们鉴定出359种与TSAT相关的蛋白质，包括TFRC（转铁蛋白受体蛋白；β，-0.455；P < 0.0001）和CRP（C反应蛋白；β，-0.355；P < 0.0001）。通路分析表明与脂质代谢、补体激活和炎症有关。与TSAT和预后之间的强烈关联相反，目前标准定义的缺铁和绝对缺铁与死亡或死亡或HF相关住院无关。无论存在功能性还是绝对缺铁，TSAT均与预后相关。
低TSAT而非铁蛋白浓度与HF的不良预后显著相关。低TSAT在射血分数保留的HF中与预后的关联更强。与炎症和脂质代谢相关的通路与HF中的低TSAT有关。
