Jamin Raúl Nicolas, Al-Kassou Baravan, Kleuker Theresa, Shamekhi Jasmin, Bartsch Benedikt, Ackerschott Ansgar, Al Zaidi Muntadher, Billig Hannah, Graef Claus Moritz, Kelm Malte, Baldus Stephan, Nickenig Georg, Latz Eicke, Zimmer Sebastian
Heart Center Bonn, Clinic for Internal Medicine II, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
Department I of Internal Medicine, University Hospital, 50937, Cologne, Germany.
Clin Res Cardiol. 2025 May 5. doi: 10.1007/s00392-025-02658-9.
Clonal hematopoiesis of indeterminate potential (CHIP) has been progressively established as a risk factor for cardiovascular disease and associated with worsened outcomes in patients with aortic valve stenosis (AVS). This cohort study aimed to evaluate the mutational landscape of CHIP and its' influence on clinical outcomes.
194 patients with AVS undergoing transcatheter aortic valve replacement (TAVR) were sequenced using a capture panel for multiple CH driver mutations and follow up conducted for three years.
We found high prevalences (77.8%) of a broad spectrum of CH-driver mutations across 38 genes, with 34% of patients fulfilling the diagnostic criteria for CHIP. Evaluating the impact of CHIP driver mutations on outcomes, the presence of CHIP was associated with mortality only when adjusting for confounding factors (HR: 2.143, 95% CI: 1.029-4.461, p = 0.042), while the presence of CH driver mutations at low VAF showed no association with mortality (p = 0.377). However, when excluding DNMT3A-CHIP, we found a significant association of CHIP with mortality in univariate (p = 0.022) and multivariable (HR: 2.976, 95% CI: 1.381-6.411, p = 0.005) analyses.
As the first study to evaluate a broad spectrum of CH driver mutations at all variant allele frequencies in the context of aortic valve stenosis, we found CHIP to be a frequent phenomenon and CH-driver mutations to be highly prevalent in patients with severe AVS. CHIP, other than DNMT3A-CHIP, was associated with increased mortality even after successful TAVR. The presence of CH driver mutations at low allele frequencies was not associated with mortality.
不确定潜能的克隆性造血（CHIP）已逐渐被确立为心血管疾病的危险因素，并与主动脉瓣狭窄（AVS）患者预后恶化相关。这项队列研究旨在评估CHIP的突变图谱及其对临床结局的影响。
对194例接受经导管主动脉瓣置换术（TAVR）的AVS患者，使用捕获面板对多个CH驱动基因突变进行测序，并进行了三年的随访。
我们发现38个基因中广泛存在CH驱动基因突变，患病率很高（77.8%），34%的患者符合CHIP的诊断标准。评估CHIP驱动基因突变对结局的影响时，仅在调整混杂因素后，CHIP的存在与死亡率相关（HR：2.143，95%CI：1.029 - 4.461，p = 0.042），而低变异等位基因频率（VAF）的CH驱动基因突变的存在与死亡率无关（p = 0.377）。然而，排除DNMT3A-CHIP后，我们在单因素（p = 0.022）和多因素（HR：2.976，95%CI：1.381 - 6.411，p = 0.005）分析中发现CHIP与死亡率有显著关联。
作为第一项在主动脉瓣狭窄背景下评估所有变异等位基因频率的广泛CH驱动基因突变的研究，我们发现CHIP是一种常见现象，CH驱动基因突变在重度AVS患者中高度流行。除DNMT3A-CHIP外，即使在成功进行TAVR后，CHIP仍与死亡率增加相关。低等位基因频率的CH驱动基因突变的存在与死亡率无关。
