BACKGROUND:
Clonal Haematopoiesis of Indeterminate Potential (CHIP) is defined as the presence of a somatic mutation-driven clonal hematopoiesis in the absence of overt hematologic disease. In the general population, carriers of CHIP mutations are twice as likely to suffer from coronary heart disease as non-carriers (Jaiswal et al. 2017). However, prevalence of CHIP and its association with risk factors and extent coronary artery disease in patients undergoing routine coronary angiography are unknown.

METHODS:
We screened 815 patients with an indication for invasive coronary  angiography at the University Hospital Freiburg out of which 178 patients had normal blood works and no concomitant malignant or inflammatory disease. In these individuals, CHIP mutation status was determined by genome sequencing of whole blood samples and correlated with the patients’ medical history, laboratory and coronary angiography findings. 

RESULTS:
53 of 178 patients carried CHIP mutations (30%). The median age was 69 years in the whole cohort, with mutation carriers being significantly older compared to non-carriers (CHIP positive: 72.5 years +/- 1.47, CHIP negative: 67.1 years +/- 0.99, p=0.001). CHIP carriers presented with elevated RDW levels in blood (CHIP positive: 13.3 +/- 0.14, CHIP negative: 13.0 +/- 0.08, p=0.030) with no other laboratory findings being significantly associated with CHIP status, similar to coronary angiogram Gensini scores which were only modestly elevated in carriers compared to non-carriers (CHIP positive: 23.3 +/- 4.3, CHIP negative: 17.9 +/- 2.1, p=0.47) in the entire cohort. Three-quarters of CHIP mutations were identified in the epigenetic regulator genes DNMT3A (54.7%) and TET2 (24.5%). Among DNMT3A and TET2 mutation carriers (n=40), those at median age or younger, presented with significantly elevated Gensini scores (CHIP positive: 40.1 +/- 10.8, CHIP negative: 16.3 +/- 2.4, p=0.044). CHIP mutation status was not associated with other cardiovascular risk factors such as smoking, arterial hypertension, diabetes and dyslipidemia, indicating that CHIP may influence CAD independently.

In a multivariate approach, the coronary artery status, measured by the number of segments showing vessel wall irregularities and number of segments needing treatment proved not to be significantly influenced by common cardiovascular risk factors. A previous myocardial infarction (MI) was more prevalent in male CHIP non-carriers, and the age at first MI was higher in CHIP positive patients above median age.

CONCLUSION AND OUTLOOK:
Our study documents that patients undergoing coronary angiography are three times more likely to carry CHIP mutations compared to the general population. CHIP associates with severe coronary artery disease particularly in younger patients in which genetic traits are highly relevant. Given the lack of our understanding of how CHIP confers cardiovascular risk, and the newly appreciated high prevalence and relevance of CHIP in daily clinical practice, our work calls for more mechanistic research in this field.