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

不确定潜力的克隆造血和尸检定义的心源性猝死的风险

• 批准号: 10531892
• 负责人: ZIAN H TSENG
• 金额: $ 80.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10531892
• 关键词: Acceleration; Address; Adult; Affect; Age; Arrhythmia; Autopsy; Belief; Biological; Blood; Blood Vessels; Blood specimen; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Case/Control Studies; Cause of Death; Cell Proliferation; Cells; Cessation of life; Clinical; Communities; Coronary Arteriosclerosis; County; Coupling; DNMT3a; Data; Diagnosis; Event; Fibrosis; Frequencies; Fright; Funding; Gene Expression; Gene Expression Profile; Gene Frequency; General Population; Genes; Genetic Transcription; Health; Heart; Heart Diseases; Hematologic Neoplasms; Hematopoiesis; Histologic; Homeostasis; Hypertrophy; Immune; Individual; Infiltration; Inflammation; Inflammatory; Ischemic Stroke; Knowledge; Leukocytes; Link; Macrophage; Macrophage Activation; Modeling; Mutation; Myocardial; Myocardium; National Heart, Lung, and Blood Institute; Outcome; Phenotype; Population; Preleukemia; Process; RNA; Reporting; Research; Resolution; Rest; Risk; Risk Factors; Role; Sampling; Sudden Death; System; Testing; Therapeutic; Time; Tissues; Trauma; atrioventricular node; cell type; cohort; comparison control; coronary fibrosis; diagnostic criteria; exome sequencing; genetic variant; immune cell infiltrate; innovation; insight; interstitial; molecular phenotype; mortality; mutant; peripheral blood; premalignant; prospective; risk stratification; sudden cardiac death; targeted sequencing; vascular inflammation

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.

项目总结/摘要 不确定潜能的克隆性造血（CHIP）是来自于造血干细胞的白细胞扩增。 不符合血液恶性肿瘤诊断标准的白血病前期克隆。最近 大规模的研究已经证明了CHIP基因突变之间的关联，主要是TET 2， DNMT 3A、ASXL 1和非癌症死亡率风险增加30-40%，缺血性心脏病风险增加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， 一般人口。机制模型提出了免疫细胞，主要是巨噬细胞， CHIP突变导致血管炎症增加和CAD加速。尽管有这些 数据表明CHIP与CV事件和总体死亡率增加显著相关， 目前尚不清楚CHIP是否与心源性猝死（SCD）有关，这是CVD最可怕的表现。 我们的NHLBI资助的正在进行的SCD后研究，自2010年以来，已对>1000例连续SCD中的97%进行了尸检。 2011年，是第一个也是唯一一个使用尸检来完善SCD的前瞻性成人SCD队列 表型与真正的心脏病和心脏病原因有关。我们最近报道说，近一半的传统- 定义的假定SCD实际上是非心源性的。重要的是，大规模外显子组测序研究 最初定义的携带率和心血管事件的风险依赖于假定的死亡原因， 通常在死亡前几年评估CHIP的存在。 我们的中心假设是，CHIP突变的常驻巨噬细胞增加了致命的风险。 在SCD后（CAD、肥大、CM）发现的SCD所有基础基质中的心律失常， 增加间质性心肌纤维化和减少电耦合。我们将通过以下方式来检验这一假设：（1） 确定SCD时CHIP的人群携带率及其相关独立风险，（2） CHIP建立增加了心脏内巨噬细胞的浸润和间质纤维化 包括传导系统，以及（3）定义CHIP 巨噬细胞增加SCD的易损心肌基质。我们预计，这种创新方法 将产生以下结果：（1）为SCD风险分层提供CHIP的潜在临床应用信息;（2） 确定巨噬细胞在心肌和血管室外传导系统中的作用 及其与SCD所有亚表型共有的纤维化促炎底物的相关性， CHIP对这一过程的调节作用;（3）测定CHIP突变体驻留细胞的RNA谱 巨噬细胞与野生型巨噬细胞的比较，以揭示CHIP对巨噬细胞的细胞环境的特异性作用。 心脏易受SCD的影响，从而潜在地鉴定用于诊断和/或治疗的新的生物靶标。 因此，拟议的研究将从根本上推进我们对CHIP如何增加CV死亡率的认识， 特别是SCD，并可能识别SCD的新风险因素。