Clonal hematopoiesis of indeterminate potential (CHIP) in cardiology

Clonal hematopoiesis of indeterminate potential (CHIP) refers to the presence of clonal genetic alterations in hematopoietic or bone marrow cells in the absence of signs of hematologic neoplasia and absence of cytopenia (Steensma et al. 2015). Large studies have demonstrated that individuals with unremarkable blood counts sometimes have gene mutations that had previously been detected predominantly in patients with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS) (Genovese et al. 2014, Jaiswal et al. 2014, Xie et al. 2014). According to the WHO classification 2022, CHIP is considered to be one of the precursor lesions (WHO 2022).

CHIP is also a possible precursor of myelodysplastic neoplasm (MDS) or other hematologic neoplasia, but has a comparatively low risk of progression (see info sheet clonal hematopoiesis of indeterminate potential (CHIP) in hematology). If clonal hematopoiesis is accompanied by undetermined cytopenia, it is referred to as CCUS (clonal cytopenia of undetermined significance).

Whole exome sequencing (i.e., sequencing of all protein-coding genes) of over 17,000 peripheral blood DNA samples, not selected for hematologic disease, revealed an association between clonal hematopoiesis and increased mortality, for which an increase in risk for coronary artery disease and ischemic insult was suspected as the cause (Jaiswal et al. 2014). In patients with unexplained erythrocytosis who do not meet diagnostic criteria for MPN, the presence of CHIP has been associated with increased cardiovascular morbidity and mortality (Wouters et al. 2020). Further studies confirmed the association between CHIP and cardiovascular disease.

In addition to cardiac disease, an association of CHIP with other vascular diseases has recently been described. In a large biobank study, individuals with CHIP were shown to be at increased risk for the occurrence of stroke, with both hemorrhagic and ischemic strokes observed (Bhattacharya et al. 2022). A detailed analysis in 248 patients with stroke before the age of 60 years showed an approximately 3-fold higher prevalence in this cohort. Notably, follow-up studies identified individual patients with myeloproliferative neoplasia requiring therapy (Mayerhofer et al. 2023).

In a cohort of 279 patients with degenerative aortic valve stenosis without hematologic disease, the impact of CHIP on overall survival after transcatheter aortic valve implantation (TAVI) was investigated. In the first 8 months after surgery, survival was significantly worse in patients with somatic mutations in the DNMT3A or TET2 genes than in patients without such mutations (p=0.012). Overall, the risk of mortality was increased 3.1-fold in the presence of mutations in the DNMT3A or TET2 genes (Mas-Peiro et al. 2020). Follow-up studies confirmed the effect of CHIP in this patient group also in long-term survival after 4 years of follow-up (Mas-Peiro et al. 2023).

Another study investigated the role of CHIP in a cohort of 200 patients with chronic heart failure after successfully revascularized myocardial infarction. CHIP was frequently detected in this patient group (18.5%) and was associated with significantly worse long-term survival (p=0.003). Also, for a combined endpoint of death and rehospitalization for heart failure, data were significantly worse for patients with mutations in the DNMT3A and TET2 genes than for patients without CHIP-associated mutations over a median observation period of 4.4 years (p=0.001). This association of CHIP with impaired long-term survival and more rapid disease progression from ischemic heart failure was evident even though there were no differences in baseline heart failure levels by New York Heart Association (NYHA) classification, Seattle Heart Failure Model (SHFM) score, left ventricular ejection fraction, or serum levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) between groups (Dorsheimer et al. 2019). Accelerated progression of heart failure could also be associated with DNMT3A or TET2 mutations (Pascual-Figal et al 2021). Prospectively, CHIP was associated with an overall 25% increased risk of heart failure occurrence (Yu et al. 2021). Again, in animal models, a causal relationship between TET2-mutated or deficient proinflammatory monocytes/macrophages in the myocardium and the progression of ischemic heart failure with increased cardiac fibrosis and decreased ejection fraction has been demonstrated (Sano et al. 2018). A mechanistic association with cardiac fibrosis and heart failure mortality has also been shown for clonal hematopoiesis with loss of the Y chromosome (Sano et al 2022).

The presence of a CHIP may arise as an incidental finding from DNA sequencing of an individual for hematologic, oncologic, or human genetic indications and requires multidisciplinary management that includes hematology/oncology, cardiology, internal medicine, clinical pathology/laboratory medicine, clinical genetics, and bioinformatics (Bolton et al. 2020, Hoermann 2022 [1], Hoermann 2022 [2]).
From a cardiology perspective, screening for the presence of CHIP is not generally recommended at this time because there is not yet sufficient evidence to specifically address cardiovascular risk in patients with CHIP. Therefore, the indication for molecular genetic analysis for the presence of CHIP in cardiology patients should only be made on a case-by-case basis when the risk situation is unclear (Jaiswal & Libby 2020). Currently, CHIP-associated risk remains unconsidered in traditional cardiovascular risk models, although it is at least of a similar magnitude to established cardiovascular risk factors. Currently, evidence-based recommendations or therapies aimed at specifically reducing CHIP-associated cardiovascular risk are still lacking. Therefore, the recommendation regarding cardiac management of patients with CHIP is individualized risk assessment and counseling to increase patient awareness and reduce overall cardiovascular risk through strict adherence to guideline-conformant primary and secondary prevention (Bolton et al. 2020, Jaiswal & Libby 2020).

For hematologic management, differential blood counts are recommended at regular intervals (initially after 3 months, later every 12 months) in patients with CHIP and normal blood counts to detect possible progression. If peripheral cytopenia of unclear cause is present in a patient with CHIP, further hematologic evaluation including bone marrow aspiration and genetic analysis is initially recommended. Subsequently, a monthly differential blood count is recommended for 3 months and a differential blood count every 3 months thereafter (Heuser et al. 2016, Haferlach & Heuser 2022) (See also clonal hematopoiesis of indeterminate potential (CHIP) in hematology).