Clonal Hematopoiesis of Indeterminate Potential and Infarct Severity in ST-Elevation Myocardial Infarction

Background and Rationale:

CHIP mutations - particularly in TET2 and DNMT3A - promote a pro-inflammatory state in hematopoietic cells. Preclinical data demonstrate that TET2-deficient macrophages exhibit exaggerated NLRP3 inflammasome activation and IL-1β secretion, while DNMT3A mutations impair immune resolution after myocardial ischemia. This enhanced inflammatory signaling may worsen myocardial ischemia-reperfusion injury (IRI), thereby increasing MVO, IMH, and infarct size in CHIP carriers presenting with STEMI.

Study Design:

Prospective, observational, single-center cohort study. No intervention beyond standard of care.

Study Population:

350 patients aged 18-75 years with STEMI undergoing primary PCI at the University Clinic of Internal Medicine III - Cardiology and Angiology, Medical University of Innsbruck. A minimum of 90 female participants will be enrolled.

Key Inclusion Criteria:

• Age 18-75 years
• STEMI with symptom onset ≤12 hours before PCI
• Successful primary PCI of culprit lesion
• Written informed consent

Key Exclusion Criteria:

• Prior myocardial infarction or known cardiomyopathy
• Known hematological malignancy
• Contraindication to CMR (pacemaker, severe claustrophobia, eGFR <30 mL/min/1.73m²)
• Cardiogenic shock requiring mechanical circulatory support
• Life expectancy <12 months due to non-cardiac cause
• Pregnancy

Assessments:

• Cardiac MRI (CMR) at 5±2 days post-PCI: MVO, IMH, infarct size (%LVMM), LV/RV ejection fraction, volumes, mass
• Targeted next-generation sequencing (NGS) for CHIP mutations (VAF ≥2%): DNMT3A, TET2, ASXL1, and other driver genes
• Single-cell RNA sequencing (scRNA-seq) of PBMCs at baseline and 12-month follow-up
• Serial blood biomarkers: hsCRP, IL-6, IL-18, NT-proBNP, troponin T, complete blood count
• Clinical follow-up visits at 12, 24, and 48 months

Primary Endpoint:

Presence of microvascular obstruction (MVO) and/or intramyocardial hemorrhage (IMH) on CMR at 5±2 days post-PCI in CHIP carriers versus non-carriers.

Secondary Endpoints:

• Infarct size (% left ventricular myocardial mass, %LVMM)
• LV and RV ejection fraction, end-diastolic/systolic volumes, myocardial mass
• MACE: all-cause mortality, non-fatal reinfarction, hospitalization for heart failure at 12, 24, and 48 months
• Changes in CHIP mutation variant allele frequency (VAF) over time
• Differential gene expression in immune cell subsets by scRNA-seq
• Biomarker trajectories (NT-proBNP, hsCRP, IL-6)

Ethics and Regulatory:

The study protocol has been approved by the Research Ethics Committee of the Medical University of Innsbruck and is conducted in accordance with the Declaration of Helsinki and ICH-GCP guidelines. All participants provide written informed consent prior to study inclusion. The study is funded by the KLiF (Klinisch-Interne Forschung) program of the Medical University of Innsbruck.

Inclusion criteria

• Diagnosis of first acute ST-elevation myocardial infarction according to current European Society of Cardiology guidelines
• Symptoms consistent with ST-elevation myocardial infarction lasting more than 30 minutes and less than 12 hours before primary percutaneous coronary intervention
• Treatment with primary percutaneous coronary intervention
• Age 18 to 75 years
• Written informed consent

Exclusion criteria

• Prior myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention
• Persistent hemodynamic instability, Killip class greater than 2 including cardiogenic shock, or resuscitated cardiac arrest not allowing cardiac magnetic resonance imaging
• Known active or prior malignancy, including hematologic malignancies or myelodysplastic syndromes
• Prior oncologic treatment with chemotherapy, radiotherapy, or radioisotopes
• Abnormal baseline complete blood count with clinically significant cytopenia, defined as leukocytes less than 3.0 x 10^9/L, platelets less than 100 x 10^9/L, or hemoglobin less than 10 g/dL
• Chronic viral infection associated with systemic inflammation
• Active autoimmune disease or chronic systemic inflammatory disorder
• Chronic kidney disease with creatinine clearance less than 30 mL/min/1.73 m2
• Contraindication to cardiac magnetic resonance imaging
• Pre-ST-elevation myocardial infarction life expectancy of less than 1 year
• Participation in an interventional trial
• Limited possibility to attend follow-up examinations, for example residence abroad
• Pregnancy