Importance Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as an independent and potent cardiovascular risk factor. As genetic sequencing becomes more widespread and the population ages, the identification of CHIP will increase substantially. Despite strong epidemiologic and mechanistic evidence linking CHIP to cardiovascular disease, no randomized trials have prospectively addressed this population. Objective To examine the major challenges in designing cardiovascular outcomes trials in CHIP and to propose a road map for advancing the evidence base for potential CHIP-targeted therapies. Evidence Review This Special Communication synthesizes current epidemiologic, mechanistic, and clinical considerations relevant to cardiovascular trial design in CHIP. Findings Multiple challenges complicate the design of cardiovascular outcomes trials in CHIP. Genetic heterogeneity across CHIP driver mutations leads to distinct biological mechanisms and cardiovascular outcomes, complicating end point selection. Cardiovascular risk also varies by clone size, creating trade-offs between broad eligibility and adequate event rates and statistical power. Differences in sequencing platforms and detection thresholds further hinder consistent risk stratification and reproducibility. Moreover, limited access to genetic testing impedes timely identification and enrollment of eligible participants. Finally, ethical concerns related to screening asymptomatic individuals, along with the advanced age and comorbidity burden of many CHIP carriers, pose challenges to recruitment, retention, and trial feasibility. Conclusions and Relevance Designing cardiovascular outcomes trials in CHIP will require moving beyond a 1-size-fits-all approach toward genotype-informed, mechanism-driven trial frameworks. Leveraging innovative trial designs, integrating CHIP analyses into ongoing cardiovascular trials, and fostering interdisciplinary multicenter collaboration will accelerate translating CHIP biology into effective cardiovascular therapies. Establishing an evidence base for managing CHIP-associated cardiovascular risk represents a critical and timely priority for precision cardiovascular medicine.

6593 Background: Despite growing observational data linking clonal hematopoiesis of indeterminate potential (CHIP) to adverse cardiovascular outcomes, the cardiovascular evaluation and management of individuals with clonal hematopoiesis remain undefined. We report the experience of a dedicated CHIP Cardiology Clinic. Methods: We conducted a retrospective review of patients evaluated in the CHIP Cardiology Clinic at the Brigham and Women’s Hospital. Baseline demographics, comorbidities, medication use, and treatment interventions were extracted from the electronic medical record. Results: Fifty-three patients were evaluated between 2020 and 2025, of whom 39 (73.6%) had clonal hematopoiesis (CH), out of which 12 (30.8%) met criteria for CHIP. Among individuals with CH, the most frequently identified mutations were D N M T 3 A (30, 76.9%), T E T 2 (23, 59.0%), and A S X L 1 (6, 15.4%). The mean age was 65.9 years (range 40-81), and 23 (58.9%) were male. Hypertension and dyslipidemia were each present in 23 (59.0%) patients. Existing cardiovascular diseases included coronary artery disease (7, 18.0%) and arrhythmias (3, 7.7%). Following evaluation in the CHIP Clinic, and shared decision-making discussion in view of the dearth of evidence regarding outcome improvement in those with CHIP, lipid-lowering therapies were initiated or increased in 28 (71.8%) patients, with statins initiated or dose escalated in 21 (53.8%) and ezetimibe in 11 (28.2%). Blood pressure medications were initiated or intensified in 5 (12.8%) patients. Ischemic evaluation was performed in 3 (7.7%) patients due to suggestive symptoms. We developed a “patient page” to acquaint the patients and families with CHIP. (https://doi.org/10.1001/jamacardio.2024.3773). Conclusions: In this first longitudinal report from a dedicated CHIP Cardiology Clinic, a substantial proportion of patients harbored somatic mutations associated with elevated cardiovascular risk. Institution of preventive cardiovascular medications, in particular lipid-lowering therapies, was a frequent intervention. These findings support the feasibility of CHIP-focused cardiovascular care but underscore the need for prospective trials to evaluate the impact of targeted preventive strategies in this population.

Clonal hematopoiesis encompasses diverse somatic mutations in hematopoietic cells, ranging from age-related expansions to mutations acquired after cytotoxic therapy, with implications for hematologic malignancy and cardiovascular disease. We characterize the spectrum of patients referred to cardiology for clonal hematopoiesis, including incidental detection during cytopenia or cancer predisposition workup, coexisting malignancy, and posttherapy surveillance. High-risk features, large clone size, multiple mutations, and specific driver genes interact with traditional cardiovascular risk factors to influence ischemic events. Contextualizing clonal hematopoiesis by detection setting, genotype, and clinical history informs individualized cardiovascular evaluation and risk mitigation, guiding mechanistically targeted preventive strategies and trial design.

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition defined by somatic mutations in hematopoietic stem cells that result in clonal expansion, without overt hematologic malignancy. It is now recognized as a potent risk factor for atherosclerotic cardiovascular disease, with emerging associations across a broader spectrum of cardiovascular phenotypes, including myocarditis, pericarditis, arrhythmias, valvular heart disease, and heart failure. The authors of this article review the epidemiology, pathophysiology, and management of this condition.

Clonal haematopoiesis of indeterminate potential (CHIP), a recently recognized, age-related cardiovascular risk factor, results from acquired, somatic mutations in a subset of known leukaemia driver genes in haematopoietic stem or progenitor cells. While prior work suggested that screening for these somatic mutations, which requires DNA sequencing, was premature due to lack of actionable evidence-based interventions, this review proposes that in light of the rapidly accumulating knowledge regarding CHIP, selective clinical testing by cardiovascular clinicians is now justified for specific high-risk individuals to improve cardiovascular risk stratification and inform preventive care. By identifying distinct mutations and estimating their burden (variant allele fraction), clinicians can understand better an individual's CHIP-related cardiovascular risk and tailor surveillance and management strategies, even before validation of targeted therapies. This review advocates a biologically driven approach to selective assessment of CHIP that leverages the advances in understanding this condition and its clinical consequences.

Background Patients with hematologic malignancies frequently have co-existing cardiovascular disease (CVD) that is either de-novo or a sequel of prior therapies. Nevertheless, clinical trials investigating anti-cancer therapies often exclude individuals with known CVD, therefore limiting the generalizability of trial results. We aimed to study temporal trends in the use of cardiovascular exclusion criteria across hematologic malignancy subtypes and treatment classes over the past 2 decades. Methods We analyzed data from the Aggregate Analysis of ClinicalTrials.gov (AACT) database, a publicly available repository of all trials registered within ClinicalTrials.gov. We identified trials initiated at or after January 1, 2020 studying interventions in Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, myeloproliferative neoplasms, and leukemia. Cardiovascular exclusions were defined as coronary artery disease, ischemic heart disease, heart failure, cardiomyopathy, arrhythmia, need for revascularization, and need for coronary artery bypass graft. Trends in the use of these exclusions were analyzed over five-year intervals using Chi-square tests. Results We identified a total of 12,194 clinical trials, of which 34.5% included at least one cardiovascular exclusion criterion. The proportion of trials with cardiovascular exclusions increased from 26.5% during 2000-2004 to 35.3% during 2020-2025 (p = 0.002). Comparing these time intervals, rates of cardiovascular exclusion increased from 16.6% to 31.7% for leukemia trials (p<0.001) and from 7.7% to 29.8% (p<0.001) for non-Hodgkin lymphoma trials. Rates of exclusion criteria remained stable for Hodgkin lymphoma, multiple myeloma, and myeloproliferative neoplasm trials. Among leukemia subtypes, chronic lymphocytic leukemia trials showed an increase in cardiovascular exclusion rate from 17.6% to 30.2% (p = 0.02) between 2000-2004 and 2020-2025. Trials investigating Bruton tyrosine kinase (BTK) and immune checkpoint inhibitors showed increases in cardiovascular exclusion rate, from 44% to 52.2% (p<0.001) and from 16.6% to 37.3 % (p<0.001), during the 20 year period. Conclusions Cardiovascular exclusions remain common in hematologic malignancy trials, limiting applicability to real-world populations. Our analysis identifies an increase in the use of cardiovascular exclusions in chronic lymphocytic leukemia trials, and particularly those investigating BTK inhibitors. The improved survival of patients with chronic lymphocytic leukemia, combined with the high prevalence of cardiovascular disease in that patient population, underscores the critical need to enroll patients with pre-existing cardiovascular disease in clinical trials to inform safe and effective treatment strategies.

Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a previously unrecognized, potent, age-related, and common risk factor for atherosclerosis. Somatic mutations in certain known leukemia driver genes give rise to clones of mutant cells in peripheral blood. The increased risk of developing hematologic malignancy does not, on its own, explain excess mortality in individuals with CHIP. Cardiovascular disease accounts for much of this gap. Experimental evidence supports the causality of certain CHIP mutations in accelerated atherosclerosis. CHIP due to mutations in different driver genes varies in their promotion of atherosclerotic events and in the region of augmented atherosclerotic involvement. For example, CHIP due to mutations in DNMT3a appears less atherogenic than CHIP that arises from TET2 or JAK2, forms of CHIP that incite inflammation. The recognition of certain CHIP mutations as promoters of atherosclerotic risk has opened new insights into understanding of the pathophysiology of this disease. The accentuated cardiovascular risk and involvement of distinct pathways of various forms of CHIP also inform novel approaches to allocation of targeted therapies, affording a step toward personalized medicine.

This JAMA Cardiology Patient Page describes clonal hematopoiesis of indeterminate potential (CHIP).

Venous thromboembolism (VTE) is common among older individuals, but provoking factors are not identified in many cases. Patients with myeloid malignancies, especially myeloproliferative neoplasms, are at increased risk for venous thrombosis. Clonal hematopoiesis of indeterminate potential (CHIP), a precursor state to myeloid malignancies, is common among the elderly and may similarly predispose to venous thrombosis. We evaluated overall and genotype-specific associations between CHIP and prevalent and incident VTE in >400,000 samples from the UK Biobank. CHIP was modestly associated with incident VTE with a hazard ratio of 1.17 (95% confidence interval (CI) 1.09-1.3; p= 0.002) but was not significantly associated with prevalent VTE with an odds ratio of 1.02 (95% CI 0.81-1.23; p= 0.81). TET2-mutant CHIP was associated with incident VTE with a hazard ratio of 1.33 (95% CI 1.05-1.69; p= 0.02). JAK2 mutations were highly associated with both prevalent and incident VTE risk with odds ratio of 6.58 (95% CI 2.65-16.29; p= 4.7 x 10-5) and hazard ratio of 4.2 (95% CI 2.18-8.08; p= 1.7 x 10-5), respectively, consistent with the thrombophilia associated with JAK2-mutant myeloproliferative neoplasms. The association between JAK2-mutant CHIP and VTE remained significant after excluding potential undiagnosed myeloproliferative neoplasms based on laboratory parameters. Compared to heterozygous factor V Leiden and heterozygous prothrombin gene mutation, JAK2-mutant CHIP was more strongly associated with VTE but was less common. These results indicate that most individuals with CHIP do not have an altered risk of thrombosis, but that individuals with JAK2-mutant CHIP have a significantly elevated risk of VTE.

Introduction: Evidence reports co-occurring risk factors between cardiovascular disease (CVD) and cancer and treatment-resultant cardiotoxicities amplifying CVD risks. Hypothesis: Given demographic disparities in CVD and cancer outcomes, we illustrated race and ethnicity-specific distributions of cardiovascular health (CVH) and quantified the contributions of socioeconomic factors to racial disparities in CVH among those with prior cancer. Methods: In the National Health Examination and Nutrition Survey 2011-2020, we identified 2628 adults aged ≥18 years with prior cancer. CVH was assessed based on the American Heart Association’s Life’s Essential 8 metrics. The Kitagawa-Blinder-Oaxaca decomposition quantified the magnitude of individual socioeconomic factors contributing to racial differences in CVH. Results: Of the 2628 US adults with prior cancer (mean[SD] age, 63.4[13.8] years; 57% women), 6.0% identified as Hispanic or Latino, 1.6% as non-Hispanic (NH) Asian, 5.2% as NH Black or African American, 84.1% as NH White, and 3.1% as uncategorized or multiple categories. NH Asian had the highest Life’s Essential 8 score (out of 100, women: 66.0; male: 69.2) in contrast to the poorest CVH in NH Black women (59.0) and Hispanic men (57.7). Overall, diet, physical activity, and body mass index were suboptimal. Across race, NH Black had the poorest blood pressure (women: 52.6, men: 41.8) and sleep (women: 74.3, men: 70.2), whereas uncategorized or multiracial group had high tobacco exposure (women: 43.6; men: 53.2). NH White women had the worst lipids (62.4), whereas NH Asian women (65.2) and Hispanic men (69.0) had the lowest glycemic score. Differences were partly explained by deprivation and low education contributing to poorer CVH among Hispanic and NH Black, whereas lower US nativity contributed to better CVH in NH Asian. Conclusions: CVH in US adults with prior cancer was suboptimal with significant racial disparities explained by socioeconomic factors.

Introduction: Cardiovascular toxicity mediated by chemotherapy drugs has important implications on the clinical outcomes of patients with breast cancer. We created a multi-component drug value framework incorporating efficacy, safety, cost, and cardiovascular toxicity data to define the overall value of standard regimens. The impact of heart failure incidence on the value score of each regimen was evaluated. Methods: The NCCN guidelines were reviewed, and four standard chemotherapy regimens used in non-metastatic HER-2 negative breast cancer were selected. PubMed was reviewed for randomized clinical trials establishing the role of each regimen. Data on the efficacy (defined as 5-year survival) and toxicity (defined as incidence of the most frequent grade 3 toxicity) profile of each regimen were extracted. Data on regimen-specific heart failure incidence at follow up were collected from prospective studies. Regimen-specific costs were derived from a recent observational cohort study. Total drug value scores (range 2.2-8.6, traditional, 2.9-11.7 upgraded) were computed and the effect of cardiotoxicity data on drug value scores was evaluated. Results: Anthracycline-containing regimens had lower mean drug value scores than anthracycline-free regimens (5.3, 61.6% versus 7.4, 86.0%) using a traditional value system based on efficacy, safety, and cost. When data on heart failure incidence were incorporated into the value assessment, anthracycline-containing regimens had lower relative value scores (mean decrease 10.7%) while anthracycline-free combinations had higher relative scores (mean increase 4.3%), compared with a traditional model. Regimen-specific value scores were modified by the addition of heart failure data. Drug value assessments that included efficacy, safety and cost showed superiority of docetaxel, adriamycin, cyclophosphamide (TAC) relative to cyclophosphamide, methotrexate, fluorouracil (CMF) (7.1, 82.6%, 6.6, 76.7%) and the addition of heart failure incidence data reversed that trend (8.6, 73.5%, 9.6, 82.0%). Conclusions: Inclusion of cardiovascular toxicity data modifies the value scores of standard chemotherapy regimens used in breast cancer and likely provides a more patient-centric value assessment.

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Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal