The role of clonal haematopoiesis in cardiovascular diseases: epidemiology and experimental studies

Abstract

Clonal haematopoiesis results from acquired mutations in haematopoietic stem and progenitor cells (HSPCs). These mutations can confer the HSPC with a competitive advantage, leading to their clonal expansion within the limiting bone marrow niche. This process is often insufficient to produce a haematologic malignancy; however, the expanding HSPC clones increasingly give rise to progeny leucocytes whose phenotypes can be altered by the somatic mutations that they harbour. Key findings from multiple human studies have shown that clonal haematopoiesis in the absence of overt haematologic alterations is common amongst the ageing population and associated with mortality and cardiovascular disease. Key findings from experimental studies have provided evidence for a causative role for clonal haematopoiesis in cardiovascular diseases, and aspects of these mechanisms have been elucidated. Whilst our understanding of the impact and biology of clonal haematopoiesis is in its infancy, analyses of some of the most commonly mutated driver genes suggest promising clinical scenarios involving the development of personalized therapies with immunomodulatory drugs that exploit the perturbation caused by the particular mutation. Herein, we review the accumulating epidemiological and experimental evidence, and summarize our current understanding of the importance of clonal haematopoiesis as a new causal risk factor for atherosclerotic cardiovascular disease and heart failure.

Keywords: ageing; cardiovascular disease; clonal haematopoiesis.

Fig. 1

Scheme of age-related clonal haematopoiesis. The accumulation of mutations in haematopoietic stem cell is an inevitable consequence of ageing. Small HSPC clones harbouring these mutations form by middle age. Some of these clones can be lost (red HSPC), whereas others are relatively stable (green, black and yellow HSPC). Some of these clones will enlarge in individuals (purple HSPC) such that a substantial fraction of progeny leucocytes can be derived from the mutant stem cells. This condition, referred to as clonal haematopoiesis, can ultimately affect leucocyte function and promote cardiovascular disease.

Fig. 2

Comparison of frequencies of known and unknown driver genes assessed by exon sequencing of candidate driver genes versus whole genome analysis. (Left) The 2014 study of Jaiswal et al. [14] involved the sequencing of exonic regions of 160 candidate driver genes, that is genes known to be recurrently mutated in haematologic malignancies. Clonal events were associated with single nucleotide variants or small insertions and deletions in 68 distinct driver genes. The 10 most frequent driver genes are displayed individually in the pie diagram, and the 58 least prevalent driver genes (15.4% of total individuals) are grouped in ‘other’. (Right) The 2017 study of Zink et al. [16] employed a nonbiased, but less sensitive, whole genome analysis method to score clonal events. Based upon genome sequence analysis, it was deduced that approximately 14% of the clonal events could be associated with known haematologic cancer driver genes, amongst which 4% could be grouped in ‘other’. However, the majority of clonal events were of unknown origin.