Clonal hematopoiesis, a condition in which acquired somatic mutations in hematopoietic stem cells lead to the outgrowth of a mutant hematopoietic clone, is associated with a higher risk of hematological cancer and a growing list of nonhematological disorders, most notably atherosclerosis and associated cardiovascular disease. However, whether accelerated atherosclerosis is a cause or a consequence of clonal hematopoiesis remains a matter of debate. Some studies support a direct contribution of certain clonal hematopoiesis-related mutations to atherosclerosis via exacerbation of inflammatory responses, whereas others suggest that clonal hematopoiesis is a symptom rather than a cause of atherosclerosis, as atherosclerosis or related traits may accelerate the expansion of mutant hematopoietic clones. Here we combine high-sensitivity DNA sequencing in blood and noninvasive vascular imaging to investigate the interplay between clonal hematopoiesis and atherosclerosis in a longitudinal cohort of healthy middle-aged individuals. We found that the presence of a clonal hematopoiesis-related mutation confers an increased risk of developing de novo femoral atherosclerosis over a 6-year period, whereas neither the presence nor the extent of atherosclerosis affects mutant cell expansion during this timeframe. These findings indicate that clonal hematopoiesis unidirectionally promotes atherosclerosis, which should help translate the growing understanding of this condition into strategies for the prevention of atherosclerotic cardiovascular disease in individuals exhibiting clonal hematopoiesis.

克隆造血是造血干细胞获得性体细胞突变导致突变造血克隆生长的一种疾病，与血液癌风险增加和非血液疾病增加有关，最明显的是动脉粥样硬化和相关心血管疾病。然而，加速动脉粥样硬化是克隆性造血的原因还是结果仍然是一个争论的问题。一些研究支持某些克隆造血相关突变通过炎症反应的加剧直接导致动脉粥样硬化，而另一些研究则认为克隆造血是动脉粥样硬化的症状而不是原因，因为动脉粥样硬化或相关特征可能会加速突变造血克隆的扩增。在这里，我们将血液中的高灵敏度 DNA 测序与无创血管成像相结合，以研究健康中年个体纵向队列中克隆造血和动脉粥样硬化之间的相互作用。我们发现，克隆性造血相关突变的存在会增加 6 年内发生新发股动脉粥样硬化的风险，而动脉粥样硬化的存在和程度都不会影响该时间范围内的突变细胞扩增。这些发现表明，克隆性造血单向促进动脉粥样硬化，这应该有助于将对这种情况的日益增长的理解转化为预防表现出克隆性造血的个体动脉粥样硬化性心血管疾病的策略。