Rise of the Mutant Clones: A Newly Recognized Risk Factor for CVD

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Up to 20 percent of people over the age of 70 have clonal hematopoiesis of indeterminate potential (CHIP), a condition that carries twice the risk of coronary heart disease and ischemic stroke, and worse outcomes after heart failure — independent of traditional cardiovascular risk factors.

The condition consists of mutant leukocytes that arise in peripheral blood from somatic mutations in hematopoietic stem cells. As the aging population grows, more patients with CHIP will present to cardiovascular specialists.

Questions remain about the best approaches for screening, assessing, and managing patients with CHIP. Together with our colleagues at other cancer research centers, we recently published a paper in the Journal of the American College of Cardiology. We explain CHIP, review the clinical questions, provide reasonable recommendations for managing cardiovascular risk in patients with CHIP, and highlight current knowledge gaps that require further research. (1)

Clonal Hematopoiesis of Indeterminate Potential

As humans age, hematopoietic stem cells can acquire somatic mutations in specific genes and differentiate into clones of mutated leukocytes in peripheral blood. The probability of having mutant clones increases with age: By the age of 70, 10 to 20 percent of individuals harbor leukocyte clones with a variant allele fraction of at least 2 percent. (2), (3)The consistent rise in the prevalence of CHIP with age suggests that the mutations are caused by impaired DNA repair and altered telomere dynamics, (4)as well as by environmental mutagens, such as radiation, tobacco smoke, or air pollutants. (5)Treatment with mutagenic drugs can also lead to the development of particular CHIP clones. (5), (6),  (7) 

CHIP is not a malignancy: It is a predisposition toward the development of leukemia. The potential is indeterminate since most individuals with CHIP will never develop leukemia. Leukemia requires the acquisition of two or three successive mutations in the same clone, a rare occurrence that arises in only 0.5 to 1 percent of CHIP carriers per year. (8)Recent studies have identified that most cases of CHIP are caused by mutations in DNMT3A, TET2, ASXL1, PPM1D, JAK2, TP53, SF3B1, and SRSF2(1) 

Mutations in DNMT3A, TET2, JAK2, and spliceosome genes — such as U2AF1 and SRSF2, and IDHI1/2 and TP53 — have a higher risk of transitioning to acute myeloid leukemia (AML). (9), (10), (11)Further, the risk of developing AML varies based on the gene that is mutated: Mutations in TP53 and U2AF1 confer a higher risk of AML or myelodysplastic syndromes, whereas mutations in DNMT3A and TET2 are associated with a lower risk. (12) 

CHIP is not a malignancy: It is a predisposition toward the development of leukemia. The potential is indeterminate since most individuals with CHIP will never develop leukemia.
Robert Sidlow Head, Division of Survivorship and Supportive Care; Associate Chair, Patient Care Operations

The current diagnostic criteria for CHIP is as follows: the absence of definitive morphological evidence of a hematological neoplasm; does not meet diagnostic criteria for paroxysmal nocturnal hemoglobinuria, monoclonal gammopathy of unknown significance (MGUS), or monoclonal B cell lymphocytosis; the presence of a somatic mutation associated with hematological cancer with a variant allele fraction of at least 2 percent; and the odds of progression to overt cancer at about 0.5 to 1 percent per year, similar to MGUS. (8) 

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CHIP and Cardiovascular Risk

A series of population studies using whole-exome sequencing revealed that individuals with CHIP had a high prevalence of cardiovascular events and deaths due to heart attack and stroke. Recent data has also shown that heart attack survivors with CHIP had increased mortality and worse heart failure outcomes. (13), (14)

Experimental evidence in cell cultures and mice suggests there is a direct causal relationship between CHIP and cardiovascular events. (3)However, the mechanisms of action appear to vary by mutation. JAK2 mutations seem to enhance the formation of plaque, (15), (16)whereas TET2 mutations are associated with enhanced expression of pro-inflammatory mediators. (17), (18)

These experimental findings have potential translational implications. There are approved strategies for treating humans with antibodies that inhibit active IL-1b, a product of the inflammasome, or IL-6, a pluripotent pro-inflammatory cytokine induced by IL-1. (19)The JAK1/2 inhibitor ruxolitinib has received approval for the treatment of primary myelofibrosis and polycythemia vera. Other JAK inhibitors are in late-stage development.

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Clinical Questions

Should we routinely screen broad populations for the presence of CHIP as we do for other cardiovascular risk factors, like hypertension and hyperlipidemia? Should we only screen adults over the age of 65 or patients with cardiovascular disease (CVD) who do not have traditional risk factors?

After identifying CHIP, how should we test and monitor patients for cardiovascular risk factors? Should all individuals with CHIP undergo cardiac testing to identify atherosclerosis or myocardial ischemia? What cardiac or vascular imaging strategies might help us monitor patients? Should cancer patients and survivors with CHIP be managed differently from those without cancer?

As genome sequencing becomes more prevalent, in both patients with cancer and other healthy populations, an increasing number of patients with CHIP will be identified. Clinicians with expertise in cardiovascular risk reduction will have to be ready to address these questions, despite the inadequacy of available clinical data to guide management.  

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Recommendations for Managing Cardiovascular Risk in CHIP

To address the increased risk of CVD associated with CHIP, we offer all our patients with CH a consultation with a cardiologist or internal medicine specialist. Currently, there is a lack of data and evidence-based recommendations targeted to decrease CHIP-associated cardiovascular risk. Furthermore, it remains unaccounted for in the traditional cardiovascular risk models, and until such data is available, the preferred management strategy is individualized risk assessment and counseling to generate awareness among patients and mitigating the overall cardiovascular risk by employing guideline-concordant primary and secondary cardiovascular prevention.

We perform a thorough assessment of traditional cardiovascular risk factors, including tobacco use, family history of premature atherosclerosis, hypertension, diabetes mellitus, chronic inflammatory diseases, and dyslipidemia. All patients undergo systolic and diastolic blood pressure measurement, physical examination (including body mass index), and a lipid panel, including LDL, triglycerides, high-density lipoprotein, high-sensitivity C-reactive protein, hemoglobin A1c, and fasting glucose. We calculate ten-year risk and, when appropriate, the lifetime risk of heart disease or stroke using the ASCVD algorithm, and we use this to guide further nonpharmacologic and pharmacologic interventions per the ACC/AHA guidelines. In patients at intermediate risk, a computed tomography–derived coronary artery calcium score is often recommended to assess for subclinical atherosclerotic disease and aid in further risk stratification.

We emphasize the ACC/AHA lifestyle recommendations, specifically to engage in at least 150 minutes of accumulated moderate-intensity aerobic physical activity per week or 75 minutes of vigorous-intensity aerobic physical activity per week (or an equivalent combination of moderate and vigorous activity). We encourage a heart-healthy diet, encouraging the intake of vegetables, fruits, whole grains, low-fat dairy products, poultry, fish, legumes, and nontropical vegetable oils and nuts and the limitation of sweets, sugar-sweetened beverages, and red meat.

The use of aspirin in primary prevention has come under considerable scrutiny in light of recent clinical trials, and we do not routinely recommend aspirin use in CHIP subjects. The specific role of aspirin in primary prophylaxis in CH is particularly salient in CHIP patients with JAK2 V617F mutations, given their heightened risk of CVD and the established role of aspirin in thromboprophylaxis in myeloproliferative neoplasms. Thus, there is an imperative for clinical studies to address this critical question.

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MSK Initiatives to Advance Care and Research

Ross Levine and researchers at MSK were the first to identify the genetic basis of clonal hematopoiesis and its connection to blood cancers in 2012. MSK opened a new clinic for people with clonal hematopoiesis in January 2018, and we continue to monitor hematologic parameters in patients with the abnormality. In addition, given the cardiovascular risk associated with CHIP, we established a novel CHIP-centric preventive cardiology clinic at MSK, as noted; it aims to comprehensively assess and manage these patients.  

Research in the Levine lab at MSK focuses on improving the understanding of the genetic causes of myeloid malignancies. The work includes elucidating and modeling the transformation from stem cells to clonal hematopoiesis and then to myeloid malignancies. 

A new clinical trial at MSK is evaluating the effect of aerobic exercise in patients with clonal hematopoiesis as well as in patients who have a higher risk of harboring circulating tumor DNA — those who have received treatment for stage III or IV breast cancer or stage III colon cancer. Researchers will investigate the impact of walking up to five times weekly for about 300 minutes total per week on biomarkers in the blood. 

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More Research Required

There is an urgent need for more research about CHIP and its association with cardiovascular disease. Outstanding questions about CHIP include whether different causal mutations vary in type, presentation, and severity of CVD, and whether common CHIP mutations should receive the standard or different management strategies to lower cardiovascular risk.

Together with our colleagues on the paper, we are hoping to establish a multicenter registry of individuals with CHIP to collect genetic, clinical, and imaging data, and we plan to follow registrants over the long term. We hope that the registry will provide a database for prospective cohort analyses and for recruiting clinical trial participants to test novel interventions.

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Robert Sidlow and Dipti Gupta are supported by a National Institutes of Health/National Cancer Institute Cancer Center Support Grant (P30 CA008748).

Dr. Levine is also supported in part by that grant (P30 CA008748). He has been a member of the supervisory board of Qiagen; has been a scientific adviser to and holds equity interest in Loxo Oncology, Imago, C4 Therapeutics, and IsoPlexis; has received research support from and been a consultant for Celgene and Roche; has received research support from Prelude Therapeutics; has consulted for Incyte, Novartis, Astellas Pharma, MorphoSys, and Janssen; and has received honoraria from Lilly and Amgen for invited lectures and from Gilead Sciences for grant reviews.

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