Abstract Body (Do not enter title and authors here):
Introduction: CHIP is associated with CAD and mortality. The prognostic relevance of CHIP for high-risk patients with confirmed CAD is unknown.

Hypothesis: CHIP variants are associated with cardiovascular (CV) events and mortality in high-risk patients with known CAD in the ISCHEMIA Trials Biorepository.

Methods: 895 ISCHEMIA and ISCHEMIA-CKD (hereafter, ISCHEMIA Trials) participants with moderate-severe ischemia and next-generation sequencing performed for CHIP variant allele fractions of ≥2% (CHIP) and ≥10% (large CHIP) were included. Unadjusted and multivariable adjusted (age, sex, diabetes, eGFR not on HD, HD, and LVEF) associations of CHIP and large CHIP with a) ISCHEMIA Trials initial phase primary endpoint (CV death, myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest, RCA) and b) ISCHEMIA Trials combined initial and extended follow-up phase (hereafter, Cumulative) endpoint of all-cause death .

Results: Median (IQR) age of sequenced participants was 67 (56 – 79) years, 19% were female, 83% white, and 6% Hispanic. Hypertension (84%), diabetes (45%) and obesity (47%) were common, 26% had an eGFR <60 ml/min/1.73m². The prevalence of CHIP and large CHIP was 23% and 7%, and both increased with age (Figure 1a). CHIP mutations in DNMT3A were detected in 106 (12%), TET2 CHIP in 44 (5%), and ASXL1 CHIP in 21 (2%) participants (Figure 1b). DNMT3A, TET2, and CREBBP mutations collectively comprised 199 (52%) of overall CHIP mutations, including individuals with multiple mutations in the same gene (N_overall = 385); 67 participants (7%) had mutations in >1 gene. Over 3.1 years of RCT follow-up there were 135 (20%), 32 (16%) and 15 (18%) primary endpoints for no CHIP, CHIP and large CHIP, respectively. Over 6.8 years of EXTEND follow-up, there were 126 (18%), 47 (23%) and 24 (29%) deaths in the no CHIP, CHIP and large CHIP groups, respectively. After multivariable adjustment there was no association between CHIP or large CHIP and CV events or mortality (Figure 1c).

Conclusion: Neither CHIP nor large CHIP was associated with adverse outcomes in 895 high-risk individuals with confirmed CAD, despite a high prevalence of these mutations.