Cardiovascular Implications of Clonal Hematopoiesis of Indeterminate Potential (CHIP)

Clonal hematopoiesis of indeterminate potential (CHIP) is increasingly identified in a variety of clinical settings, with patients often referred to a specialized cardiologist to assess and manage cardiovascular risk. Guidance should depend on the setting in which the abnormality was detected, the specific mutation and clone size, and individual clinical factors.

So advise experts in a review paper describing the range of patients with CHIP who are referred to cardiovascular clinicians. The article presents four prototypical CHIP cases, using representative clinical scenarios to translate current evidence into practical recommendations for cardiovascular management. It was recently published in Circulation: Genomic and Precision Medicine (2026:19[3]:e005544).

“The categories of patients we describe emerged from our clinical observations and increasing understanding of the biological underpinnings and cardiovascular implications of CHIP,” says Cleveland Clinic cardiologist and hematologist-oncologist Ohad Oren, MD, MPH. “The classification is helpful to inform personalized management of this heterogeneous population.”

Dr. Oren (shown in the photo above with a patient) co-authored the review with Dr. Peter Libby of the Massachusetts General Brigham in Boston; both are pioneers in the field of clonal hematopoiesis.

What is CHIP?

CHIP stem cell mutations give rise to abnormal cell clones that are detectable in the peripheral blood. These somatic mutations are acquired with age: They are rare before age 40, have a prevalence of less than 8% in individuals in their 60s and are present in about one in four people in their 80s. A CHIP mutation is more likely to arise in people who use tobacco or have other mutagenic exposures during their lifetime.

Known primarily as a precursor of hematologic malignancies, CHIP is now also understood to be an important cardiovascular risk factor, likely owing to ramping up of inflammatory processes.

More than 45 different CHIP mutations have been identified. Some are associated with increased cardiovascular risk, especially TET2, ASXL1, TP53, PPM1D and JAK2 variants. Some have been linked to accelerated atherosclerosis, atrial fibrillation, venous thromboembolism and peripheral arterial disease. Clone size is measured as variant allele frequency: At least 2% is the threshold used to define the presence of CHIP, and at least 10% is considered large.

Clinical categories

While testing for CHIP is not widespread and not recommended for the general population, certain situations warrant genomic investigation. The review describes four types of patients identified with CHIP — some of whom are otherwise healthy — who may be referred to a cardiologist for evaluation and management of cardiovascular risk.

Category 1: Clonal hematopoiesis (CH) associated with cytopenia workup

About one-quarter of patients who undergo investigation of a low blood cell count have clonal cytopenia of unknown significance (CCUS). Similar to CHIP, CCUS is a potential precursor for myeloid neoplasms with distinct genetic profiles. The most common mutations are DNMT3A, TET2 and SRSF2. High-risk CCUS is associated with significant cardiovascular morbidity.

Category 2: CH discovered during cancer predisposition evaluation

Individuals at high risk for cancer because of family history or other predisposing factors often are evaluated with a multicancer gene panel to test for germline variants. Likely pathogenic germline mutations – especially in the APC, CHEK2 and ATM genes – have been identified as risk factors for developing CH. Additionally, some CH genotypes occur more often in patients with certain germline mutations. Among patients with mosaic chromosomal alterations, rates of CH have been found to be about 50%.

Category 3: CH found in cancer patients

Because patients with cancer often undergo genetic testing to identify therapeutic targets, acquired somatic mutations may be incidentally discovered. The frequency of CH varies widely by cancer type; those with high cellular turnover (e.g., gastrointestinal and lung cancers) are more likely to develop CHIP variants.

Category 4: CH after cytotoxic cancer therapy

CHIP variants may be discovered years after cancer therapy. Cytotoxic radiation and chemotherapy increase the risk of developing CH mutations, especially in DNA damage-response genes (e.g., TP53, PPM1D and CHEK2). The PPM1D variant has been linked to accelerated multiarterial atherosclerosis, as well as to atrial fibrillation, and TP53 mutations are associated with increased mortality.

CHIP management

“Clonal hematopoiesis is revealing important connections between cancer biology, aging and cardiovascular disease,” notes Jame Abraham, MD, Chair of Hematology and Medical Oncology in Cleveland Clinic Cancer Institute. “Insights like those from Dr. Oren’s review paper are helping us move toward a more proactive, personalized approach to patient care.”

Indeed, Dr. Oren emphasizes that cardiovascular management of patients with CHIP should be individualized, as clinical implications vary according to the mutated gene, clone size and overall clinical context. He assesses cardiovascular risk in patients with CH by considering the following high-risk features:

• Presence of high-risk mutations (TET2, JAK2 and TP53)
• Large variant allele frequency (i.e., > 10%)
• Expanding clone size over time
• Presence of more than one mutation
• Established cardiovascular disease
• Traditional cardiovascular risk factors
• Age over 65

“In addition, understanding the context in which CHIP was identified is important when assessing risk,” he explains. “The patient’s hematologic picture, cancer history and cardiovascular history, on top of the genomic data, all influence management strategy when determining how intensively to pursue cardiovascular risk reduction.”

As an example, he notes that for a patient at very elevated risk, such as having CCUS with a TET2 mutation with variant allele frequency greater than 10%, he treats aggressively to tightly control cardiovascular risk factors, such as aiming for an LDL cholesterol target below 55 mg/dL.

No guidelines exist for regular surveillance of CH, but repeat sequencing is often performed in patients with CCUS, cytotoxic exposure or worsening blood abnormalities.

A considerable learning curve

Dr. Oren is one of a small number of cardiologists studying the implications of CHIP for cardiovascular health. “We are privileged to have easy access to Dr. Oren’s highly specialized expertise at Cleveland Clinic through the new CHIP Cardiology Clinic he has established here,” notes Venu Menon, MD, Section Head of Clinical Cardiology. “His fellowship training in both hematology-oncology and cardiology positions him as a colleague we can refer patients to with confidence regardless of when or how their clonal hematopoiesis may be identified.”

For his part, Dr. Oren emphasizes the need for more data — facilitated by collaboration among large academic cancer centers — to further characterize CHIP variants and management strategies.

“Cardiologists don’t usually get much training about bone marrow and somatic mutations, but we cannot escape their impact,” Dr. Oren concludes. “We are just beginning to understand the effects of somatic variants on cardiovascular health, and we expect this field to expand exponentially as genetic testing becomes more available.”