Clonal Hematopoiesis Of Indeterminate Potential In Patients With ACS Undergoing PCI In The Absence Of Traditional Cardiovascular Risk Factors

Objectives1.To investigate the long-term clinical outcomes of acute coronary syndrome(ACS)patients undergoing percutaneous coronary intervention(PCI)in the absence of traditional cardiovascular risk factors(CVRFs).2.To investigate the prevalence of clonal hematopoiesis of indeterminate potential(CHIP)among patients with ACS undergoing PCI without traditional CVRFs and further assess the potential prognostic significance of CHIP-related mutations in this cohort.Methods1.The Optimal anti Platelet Therapy for Chinese patients with Coronary Artery Disease(OPT-CAD)registry study was a large-scale,multicenter,prospective,real-world practice observational study.This study was conducted in 14,032 consecutive CAD patients who were survived until hospital discharge between January 2012 and March 2014 at 107 centers in China.We selected patients with ACS undergoing PCI completing 5 year follow up from OPT-CAD registry study.The clinical outcomes among patients with CVRFs and at least one CVRFs cohorts were compared.The primary endpoint was major adverse cardiac or cerebral events(MACCEs),defined as a composite of all-cause death,nonfatal myocardial infarction,nonfatal stroke or unstable angina requiring unplanned revascularization.An exploratory multivariable Cox proportional hazards regression analysis was performed to identify demographic and clinical independent predictors of the endpoint.2.Whole-exome sequencing was performed to detect the presence of CHIP in 244 patients underwent PCI for the treatment of ACS,consist of 183 without CVRFs and 61 with CVRFs(3:1 ratio).The association between CHIP-related mutations and MACCEs was analyzed in patients without CVRFs.Results1.Among 5,688 patients with ACS undergoing PCI,392(6.9%)were CVRFs-free cohort and 5,296(93.1%)were at least one CVRFs cohort.During 5-year follow-up,the MACCEs occurred in 72 patients in the CVRFs-absent ACS cohort and 1,051 patients in the CVRFs-present ACS cohort.There was no significant difference in the rate of MACCEs between cohorts(18.4% vs.19.8%,log-rank P =0.57).Multivariable Cox proportional hazards regression analysis indicated that age was independent predictor of MACCEs in the CVRFs-absent ACS cohort(HR,1.03;95% CI,1.01-1.05;P =0.005).2.The prevalence of CHIP was significantly greater in patients without traditional CVRFs compared to patients with CVRFs(20.1% vs.8.6%,P =0.04).The somatic mutations most frequently occurred in the genes DNMT3A(20 variants),TET2(6 variants),and ASXL1(4 variants).Clinical outcomes at median 635 follow-up days showed that DNMT3A/TET2 /ASXL1-CHIP mutations were associated with significantly higher risk of MACCEs,compared with non-CHIP carriers in the CVRFs-absent ACS cohort(26.1% vs.4.2%,log-rank P =0.001).Multivariable Cox proportional hazards regression analysis showed that DNMT3A/TET2/ASXL1-CHIP mutations were independent predictors of adverse clinical outcomes(HR,4.02;95% CI,1.24-13.05;P =0.02).Conclusions1.Among ACS patients treated with PCI,the CVRFs-absent patients cohort,compared with those with CVRFs,a similar risk of recurrent cardiovascular events was observed at 5 year.2.CHIP prevalence is higher in patients with ACS undergoing PCI without traditional CVRFs,compared to those with CVRFs,and the most frequent CHIP-driver mutations DNMT3 A,TET2,and ASXL1 are significantly associated with increased risk of recurrent cardiovascular events.These data are helpful to detect CHIP precisely.While further studies are warranted to test whether targeting specific inflammatory pathways might provide a valuable strategy to precision medicine in patients carrying specific mutations.