Clonal Hematopoeisis of Indeterminate Potential and Risk of Autopsy-defined Sudden Cardiac Death

项目摘要/摘要 克隆性造血潜能不定(CHIP)是一种白细胞的扩增。 具有白血病前期潜在性且不符合血液系统恶性肿瘤诊断标准的克隆。近期 大规模研究已经证明了芯片基因突变之间的关联，主要是TET2， DNMT3A、ASXL1和非癌症死亡风险增加30%-40%，缺血风险增加2倍 中风和冠状动脉疾病(CAD)，以及心血管(CV)死亡的累积增加 普通人口。机制模型提出免疫细胞，主要是巨噬细胞的表型转换， 芯片突变会导致血管炎症增加，加速冠心病。尽管如此 数据表明，CHIP与心血管事件和总死亡率的增加显著相关，它 尚不清楚CHIP是否与心源性猝死(SCD)有关，SCD是心血管疾病最可怕的表现。 我们由NHLBI资助的正在进行的SCD后研究，已经解剖了连续1000个SCD中的97% 2011年，是第一个也是唯一一个预期的未经选择的成人SCD队列，使用尸检来完善SCD 从表型到真正的心脏和心律失常原因。我们最近报道了近一半的常规- 明确推定的SCD实际上是非心脏的。重要的是，大规模的外显子组测序研究 最初定义的心血管事件的携带率和风险取决于假定的死亡原因和 通常在死亡前几年评估芯片的存在。 我们的中心假设是，芯片突变驻留的巨噬细胞增加了死亡的风险 在SCD后(冠心病、肥厚、CM)中发现SCD所有基础底物的心律失常 增加间质心肌纤维化，减少电耦合。我们将通过以下方式检验这一假设：(1) 确定SCD时芯片的种群携带率及其相关的独立风险，(2) 证实CHIP增加了心脏内巨噬细胞的渗透和间质纤维化 间质，包括传导系统，以及(3)定义芯片的转录机制 巨噬细胞增加了SCD的易损心肌底物。我们预计，这种创新的方法 将产生以下结果：(1)提示芯片用于SCD风险分层的潜在临床应用；(2) 确定巨噬细胞在血管间隔外的心肌和传导系统中的作用 及其与SCD所有亚型共同的纤维化致心律失常底物的相关性，以及 CHIP对这一过程的调控作用；(3)测定CHIP-突变体驻留的RNA图谱 巨噬细胞与野生型巨噬细胞对比，揭示芯片对细胞环境的特定影响 因此，我们有可能为诊断和/或治疗寻找新的生物靶点。 因此，拟议的研究将从根本上提高我们对CHIP如何增加心血管死亡率的了解， 特别是SCD，并有可能确定SCD的新危险因素。

PROJECT SUMMARY/ABSTRACT Clonal hematopoiesis of indeterminate potential (CHIP) is the expansion of leukocytes derived from a clone with pre-leukemic potential that does not fulfill diagnostic criteria for a hematologic malignancy. Recent large-scale studies have demonstrated an association between mutations in CHIP genes, mostly in TET2, DNMT3A, ASXL1, and a 30-40% increased risk of non-cancer mortality, a 2-fold increased risk of ischemic stroke and coronary artery disease (CAD), and a cumulative increase in cardiovascular (CV) death in the general population. Mechanistic models propose a phenotypic switch in immune cells, chiefly macrophages, with CHIP mutations leading to increased vascular inflammation and accelerated CAD. Despite these data suggesting that CHIP is significantly associated with increased CV events and overall mortality, it is unknown whether CHIP is associated with sudden cardiac death (SCD), the most feared manifestation of CVD. Our NHLBI-funded ongoing POST SCD Study, which has autopsied 97% of >1000 consecutive SCDs since 2011, is the first and only prospective unselected adult SCD cohort to use autopsy to refine the SCD phenotype to true cardiac and arrhythmic causes. We recently reported that nearly half of conventionally- defined presumed SCDs were in fact non-cardiac. Importantly, the large-scale exome sequencing studies that initially defined the carrier rates and risk of a cardiovascular event relied on presumed causes of death and often assessed for the presence of CHIP years prior to death. Our central hypothesis is that CHIP-mutant resident macrophages increase the risk of fatal arrhythmias across all underlying substrates of SCD found in POST SCD (CAD, hypertrophy, CM) by increasing interstitial myocardial fibrosis and decreasing electrical coupling. We will test this hypothesis by: (1) determining the population carrier rate of CHIP at the time of SCD and its associated independent risk, (2) establish that CHIP increases the infiltration of macrophages and interstitial fibrosis within the cardiac interstitium, including the conduction system, and (3) define the transcriptional mechanism by which CHIP macrophages increase vulnerable myocardial substrate for SCD. We anticipate that this innovative approach will yield the following outcomes: (1) inform potential clinical use of CHIP for SCD risk stratification; (2) establish the role of macrophages on myocardium and conduction system beyond the vascular compartment and its correlation with fibrotic arrhythmogenic substrate common to all sub-phenotypes of SCD, and the modulating effect of CHIP on this process; (3) determine the RNA profiles of CHIP-mutant resident macrophages vs. wildtype macrophages to reveal insights into CHIP-specific effects on the cellular milieu of hearts vulnerable to SCD to thus potentially identify new biologic targets for diagnosis and/or therapeutics. Thus, the proposed research will fundamentally advance our knowledge of how CHIP increases CV mortality, specifically SCD, and potentially identify a new risk factor for SCD.