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

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

Clonal Hematopoiesis of Indeterminate Potential (CHIP) refers to the age-related expansion of hematopoietic stem cell clones carrying somatic mutations in leukemia-associated driver genes (e.g., DNMT3A, TET2, ASXL1) in the absence of a hematological malignancy. CHIP has been identified as an independent cardiovascular risk factor associated with increased rates of myocardial infarction, stroke, and cardiovascular mortality, likely mediated through enhanced inflammatory signaling in mutant macrophages and monocytes.

ST-elevation myocardial infarction (STEMI) is a life-threatening emergency requiring immediate reperfusion by primary percutaneous coronary intervention (PCI). Despite successful reperfusion, adverse cardiac remodeling and heart failure may occur depending on myocardial injury severity, microvascular obstruction (MVO), and intramyocardial hemorrhage (IMH) - phenomena substantially driven by ischemia-reperfusion injury and the inflammatory response.

The CHIP in STEMI study is a prospective, observational, single-center cohort study at the Medical University of Innsbruck investigating whether CHIP - detected by targeted next-generation sequencing - is associated with greater infarct severity and worse cardiac outcomes in STEMI patients undergoing primary PCI. The primary endpoint is the presence of MVO and/or IMH on cardiac MRI (CMR) at 5±2 days post-PCI. Secondary endpoints include infarct size, left and right ventricular function, major adverse cardiovascular events (MACE), and immune cell transcriptome profiling by single-cell RNA sequencing.

350 patients (18-75 years, minimum 90 female) will be enrolled over 36 months and followed for 4 years (2026-2030).

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:

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