Aurora Semerano, MD
Bhattacharya R, Zekavat SM, Haessler J, Fornage M, Raffield L, Uddin MM, Bick AG, Niroula A, Yu B, Gibson C, et al. Clonal Hematopoiesis Is Associated With Higher Risk of Stroke. Stroke. 2021.
Clonal hematopoiesis of indeterminate potential (CHIP) consists of a clonal expansion of circulating blood cells that arises from somatic mutations in hematopoietic stem cells. This condition usually does not entail abnormal blood cell counts and is common in older individuals, since it has been detected by DNA sequencing in >10% of people aged 70+ years. While carrying a relatively modest risk of developing hematological malignancy, from 2014 onwards CHIP has been unexpectedly and increasingly recognized as an independent, non-traditional risk factor for cardiovascular diseases and atherosclerosis, underlying the important interplay between aging, inflammation, and cardiovascular health. Interestingly, CHIP is determined by mutations in a handful of genes, which are currently under active investigations in experimental models. For example, accelerated atherosclerosis and increased release of inflammatory cytokines have been found in mice that bear TET2-deficient leukocytes. The relationship between CHIP and stroke risk was first reported in 2014 by Jaiswal et al.1 Indeed, by analyzing two cohorts of ~3000 patients, the presence of a somatic mutation was associated with an increased risk of ischemic stroke with a hazard ratio of 2.6 (95% CI, 1.4 to 4.8).
In the article by Bhattacharya et al. recently published in Stroke, the authors aimed at expanding the knowledge about the association between CHIP and risk of cerebrovascular events, taking into account both ischemic and hemorrhagic strokes, as well as stroke etiology. A total of 86,178 individuals from 8 prospective cohorts or biobanks were included. The overall prevalence of CHIP at baseline was 6%. CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14; 95% CI, 1.03–1.27). Unexpectedly, this relationship was primarily driven by a 24% increased odds of hemorrhagic stroke, particularly subarachnoid hemorrhage. Though CHIP was not found to be associated with ischemic stroke overall, in exploratory analyses from one female patient cohort, CHIP was more strongly associated with small vessel disease than with large artery atherosclerosis or cardioembolic etiologies. When analyzing mutations in specific CHIP genes, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke.
Further investigations with a mechanistic approach are required to shed light on the possible processes underlying these interesting and unexpected findings. It could be speculated that common pathogenetic mechanisms of vascular inflammation may account for the observed CHIP associations in small vessel stroke and intracerebral hemorrhage. Notably, subarachnoid hemorrhage usually occurs at a fairly young age compared to other hemorrhage subtypes, and further studies are needed to confirm the association with CHIP, as well as to evaluate the role of inflammatory pathways in aneurysm rupture and/or cerebral amyloid angiopathy. It could be supposed that functional alterations of immune cells in CHIP may result in an impairment of hemostatic and coagulative function, encompassing an increase of both thrombotic and bleeding risk, similarly to what happens in hematologic disorders. Also, the lack of association in this study between CHIP and atherosclerotic stroke subtype is somehow surprising. It should be considered that different mechanisms leading to ischemic stroke are possible in atherosclerotic disease; moreover, the classification of stroke etiology has limitations since it is presumptive in many cases, and likely distinctive pathogenetic roles exist for each genetic CHIP variant. Experimental forces are joining2 to unravel the potential mechanisms by which CHIP mutations augment cardiovascular risk, including macrophage activation and erythrophagocytosis, increased platelet-leukocyte aggregation, aberrant neutrophil function, and failed inflammation resolution. Similarly, efforts to collect specimens, as well as clinical, imaging and laboratory data, from individuals in multicenter registries are advisable.3 The discovery of CHIP is recent, and many unanswered questions remain. Refinement of the mechanistic effects linking clonal hematopoiesis and cerebrovascular diseases will be pivotal to advance research, to identify new methods of risk stratification, and to prospect novel immune therapeutic interventions in stroke.
1 Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, McConkey M, Gupta N, Gabriel S, Ardissino D, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377:111–121. doi: 10.1056/NEJMoa1701719.
2 Hidalgo A, Tall AR. Leducq Transatlantic Network on Clonal Hematopoiesis and Atherosclerosis. Circ Res. 2019 Feb 15;124(4):481-483. doi: 10.1161/CIRCRESAHA.119.314677.
3 Libby P, Sidlow R, Lin AE, Gupta D, Jones LW, Moslehi J, Zeiher A, Jaiswal S, Schulz C, Blankstein R, Bolton KL, Steensma D, Levine RL, Ebert BL. Clonal Hematopoiesis: Crossroads of Aging, Cardiovascular Disease, and Cancer: JACC Review Topic of the Week. J Am Coll Cardiol. 2019 Jul 30;74(4):567-577. doi: 10.1016/j.jacc.2019.06.007.