Clonal Haematopoiesis and Incident Heart Failure: Mechanisms and Clinical Implications

Abstract

Background: Clonal haematopoiesis of indeterminate potential (CHIP) is a widespread age related disease that is spontaneously induced by somatic mutations in haematopoietic stem cells which permit mutant clones to emerge as competitive. Even though CHIP is a known risk factor of atherosclerotic cardiovascular disease, its role in causing incident heart failure (HF), and the biological mechanisms between mutated clones and myocardial dysfunction, are not completely understood yet.

Purpose: This is a review of developing evidence on the association between CHIP and incident HF in relation to mechanistic pathways and new clinical implications of risk prediction and treatment.

Methods Recent epidemiologic, genomic, and translational literature was examined to determine the relationship between CHIP-related mutations, especially, TET2, DNMT3A, ASXL1 and JAK2 mutations and HF. To demonstrate ways of causal inflammatory and myocardial remodelling through complementary preclinical studies were examined.

Findings: Numerous large, population-based studies indicate that CHIP participants are at high risk of developing HF, which is not dependent on conventional risk factors of cardiovascular diseases. Mechanistic investigations demonstrate that CHIP-related mutant macrophages are hyper-proinflammatory, particularly through IL-1 0 IL-6 pathways, that favor undesired myocardial remodeling, interstitial fibrosis, and dysfunctional ventricular function. The TET2 and JAK2 mutants also show the best correlations with the amplified signals of inflammatory pathways and endothelial dysfunction. A dose-response effect is also gaining strength with larger clone sizes (increased variant allele fractions) being associated with increased HF risks.

Conclusions: CHIP is a significant non-conventional predictor of HF risks, which is mostly imposed by maladaptive inflammatory signaling by the mutated myeloid cells. The introduction of CHIP status into the cardiovascular risk assessment can potentially allow determining vulnerable populations sooner, and future research should examine the specific anti-inflammatory therapies and the best screening strategies in elderly patients at risk.