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Impact of Carrying DNMT3A or TET2 Mutations on Plaque Characteristics and Prognosis in Patients With STEMI Based on
Qianhui Sun1,2, Shengfang Wang1,2, Ming Zeng1,2
1Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Province, China (Q.S., S.W., M.Z., M.L., C.Z., B. Yi, S.H., B. Yu, H.J.).
Insights
Clonal hematopoiesis mutations in DNMT3A or TET2 genes are linked to vulnerable coronary plaques and increased cardiovascular events in ST-segment-elevation myocardial infarction patients. TET2 mutations indicate a worse prognosis than DNMT3A mutations alone.
Area of Science:
- Cardiology
- Genetics
- Oncology
Background:
- Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging risk factor for coronary heart disease.
- DNMT3A and TET2 are the most frequently mutated genes in CHIP.
- This study investigates the impact of CHIP-associated DNMT3A/TET2 mutations on coronary plaque characteristics and prognosis in ST-segment-elevation myocardial infarction (STEMI) patients.
Purpose of the Study:
- To evaluate the association between DNMT3A/TET2 mutations and coronary plaque vulnerability in STEMI patients.
- To assess the prognostic significance of these mutations regarding major adverse cardiovascular events (MACE).
- To compare the outcomes associated with DNMT3A and TET2 mutations individually and combined.
Main Methods:
- Enrollment of consecutive STEMI patients undergoing optical coherence tomography (OCT) between May 2017 and May 2019.
- Targeted deep exome sequencing of peripheral blood to identify DNMT3A/TET2 mutations (variant allele frequency ≥2%).
- Primary endpoint defined as MACE (all-cause death, nonfatal MI, nonfatal stroke, revascularization).
Main Results:
- 12.3% of 628 STEMI patients carried DNMT3A/TET2 mutations.
- Mutation carriers exhibited more vulnerable plaque features on OCT (higher macrophage proportion, smaller lumen area, thinner fibrous cap, higher lipid index).
- MACE rates were significantly higher in mutation carriers (39.5% vs. 19.9%; P<0.001) during a median follow-up of 2.4 years.
- DNMT3A/TET2 mutations (aHR, 1.91) and TET2 mutations specifically (aHR, 3.57) independently predicted MACE.
Conclusions:
- STEMI patients with DNMT3A/TET2 mutations present with more vulnerable coronary plaques.
- These mutations are associated with a significantly increased risk of MACE in STEMI patients.
- TET2 mutations confer a worse prognosis compared to DNMT3A mutations alone in this cohort.
Background:
Clonal hematopoiesis of indeterminate potential is a novel, nontraditional risk factor linked to coronary heart disease. DNMT3A and TET2 are the 2 most prevalent clonal hematopoiesis of indeterminate potential-associated driver genes. This study aims to evaluate their effects on plaque characteristics and prognosis in patients with ST-segment-elevation myocardial infarction.
Methods:
Consecutive patients with ST-segment-elevation myocardial infarction (May 2017-May 2019) undergoing routine optical coherence tomography were enrolled. Targeted deep exome sequencing of peripheral blood (custom panel targeting DNMT3A and TET2) identified mutations (with a threshold variant allele frequency ≥2%). The primary end point was major adverse cardiovascular events, defined as a composite end point that includes all-cause death, nonfatal myocardial infarction, nonfatal stroke, and revascularization due to clinical ischemic events.
Results:
Among 628 patients, 12.3% were identified as carriers of DNMT3A or TET2 gene mutations. Patients with DNMT3A/TET2 mutations were older (62.5 versus 55.6 years; P<0.001), while the 2 groups showed comparable prevalence rates of hypertension (48.1% versus 43.2%), diabetes (22.1% versus 22.3%), and dyslipidemia (53.2% versus 61.7%). Carriers demonstrated greater plaque vulnerability characteristics on optical coherence tomography, including a higher macrophage proportion, smaller minimal lumen area, thinner fibrous cap, and higher lipid index. During a median follow-up of 2.4 years (interquartile range 2.0-3.0), major adverse cardiovascular events rates were significantly higher in the mutation group (39.5% versus 19.9%; P<0.001). Both DNMT3A/TET2 mutations (adjusted hazard ratio, 1.91 [95% CI, 1.19-3.07]; P=0.008) and TET2 mutations specifically (adjusted hazard ratio, 3.57 [95% CI, 1.78-7.17]; P<0.001) independently predicted major adverse cardiovascular events occurrence in patients with ST-segment-elevation myocardial infarction.
Conclusions:
Patients with ST-segment-elevation myocardial infarction and DNMT3A/TET2 mutations exhibit vulnerable characteristics in their coronary plaques, along with an increased risk of experiencing major adverse cardiovascular events. Moreover, carrying TET2 mutations confers a worse prognosis compared with solely having DNMT3A mutations.
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