Importance:Clonal hematopoiesis of indeterminate potential (CHIP) is the age-related clonal expansion of hematopoietic stem cells with leukemia-associated mutations. Certain CHIP mutations promote atherosclerosis and heart failure through immune-related pathways. Objective:To test whether CHIP is associated with the development of myocarditis and pericarditis. Design, Setting, and Participants:This observational population-based cohort study used data from the UK Biobank. Enrollment occurred between 2006 and 2010. Participants with whole-exome sequencing, no prevalent cardiovascular disease or hematological malignancy, and complete covariate data were included. Follow-up occurred for a median of 13.6 (IQR, 12.8-14.2) years. Analyses were conducted from November 2024 to July 2025. Exposures:Any CHIP (variant allele frequency [VAF] ≥2%) and large CHIP (VAF ≥10%) constituted coprimary study exposures. Secondary analyses considered DNMT3A and TET2 CHIP as separate exposures. Main outcomes and measures:The primary outcome was a composite of incident myocarditis and pericarditis. Cox regression tested associations of CHIP with myocarditis and pericarditis, adjusting for age, sex, race and ancestry, and cardiovascular risk factors. Secondary analyses considered myocarditis and pericarditis as separate outcomes. Additional analyses compared associations of CHIP with myocarditis and pericarditis with those with other cardiovascular diseases, and tested the bidirectional associations between CHIP and noncardiac immune-mediated inflammatory diseases. Results:Among 335 426 participants (mean age, 56.1 years; 185 429 female [55.3%] and 149 997 male [44.7%]), 11 057 had any CHIP (3.3%), 7271 had large CHIP (2.2%), and 382 developed myocarditis or pericarditis (0.11%). Any and large CHIP were associated with multivariable-adjusted hazard ratios of 1.75 (95% CI, 1.14-2.68; P = .01) and 2.07 (95% CI, 1.28-3.33; P = .003), respectively, for the primary composite outcome of incident myocarditis and pericarditis. Increased risks were observed for DNMT3A and TET2 CHIP, with hazard ratios of 2.22 (95% CI, 1.17-4.21; P = .01) for DNMT3A with pericarditis and 3.65 (95% CI, 1.16-11.49; P = .03) for TET2 with myocarditis. CHIP associated with myocarditis and pericarditis more strongly than with other cardiovascular diseases (eg, coronary artery disease and heart failure). Any CHIP was also associated with 1.27-fold risk (95% CI, 1.16-1.39; P < .001) of developing noncardiac immune-mediated inflammatory diseases, without evidence for reverse causation. Conclusions and Relevance:In this study, CHIP was a strong risk factor for myocarditis and pericarditis among middle-aged adults. Targeting CHIP and its downstream pathways may represent a strategy for preventing or treating pericarditis and myocarditis.

Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer insights into downstream clinical consequences. Here we explore these patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 participants (3881 with CHIP) from TOPMed and UK Biobank (UKB) with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2917 proteins by Olink in UKB), we identify 32 and 345 proteins from TOPMed and UKB, respectively, associated with CHIP and most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations show substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangle causal proteomic perturbations from TET2 CHIP. Lastly, we identify plasma proteins shared between CHIP and CAD.

BACKGROUND:Clonal hematopoiesis of indeterminate potential (CHIP), a common age-associated phenomenon, associates with increased risk of both hematological malignancy and cardiovascular disease. Although CHIP is known to increase the risk of myocardial infarction and heart failure, the influence of CHIP in cardiac arrhythmias, such as atrial fibrillation (AF), is less explored. METHODS:CHIP prevalence was determined in the UK Biobank, and incident AF analysis was stratified by CHIP status and clone size using Cox proportional hazard models. Lethally irradiated mice were transplanted with hematopoietic-specific loss of Tet2, hematopoietic-specific loss of Tet2 and Nlrp3, or wild-type control and fed a Western diet, compounded with or without NLRP3 (NLR [NACHT, LRR {leucine rich repeat}] family pyrin domain containing protein 3) inhibitor, NP3-361, for 6 to 9 weeks. Mice underwent in vivo invasive electrophysiology studies and ex vivo optical mapping. Cardiomyocytes from Ldlr-/- mice with hematopoietic-specific loss of Tet2 or wild-type control and fed a Western diet were isolated to evaluate calcium signaling dynamics and analysis. Cocultures of pluripotent stem cell-derived atrial cardiomyocytes were incubated with Tet2-deficient bone marrow-derived macrophages, wild-type control, or cytokines IL-1 beta (interleukin 1 beta) or IL-6 (interleukin 6). RESULTS:Analysis of the UK Biobank showed individuals with CHIP, in particular TET2 CHIP, have increased incident AF. Hematopoietic-specific inactivation of Tet2 increases AF propensity in atherogenic and nonatherogenic mouse models and is associated with increased Nlrp3 expression and CaMKII (Ca2+/calmodulin-dependent protein kinase II) activation, with AF susceptibility prevented by inactivation of Nlrp3. Cardiomyocytes isolated from Ldlr-/- mice with hematopoietic inactivation of Tet2 and fed a Western diet have impaired calcium release from the sarcoplasmic reticulum into the cytosol, contributing to atrial arrhythmogenesis. Abnormal sarcoplasmic reticulum calcium release was recapitulated in cocultures of cardiomyocytes with the addition of Tet2-deficient macrophages or cytokines IL-1 beta or IL-6. CONCLUSIONS:We identified a modest association between CHIP, particularly TET2 CHIP, and incident AF in the UK Biobank population. In a mouse model of AF resulting from hematopoietic-specific inactivation of Tet2, we propose altered calcium handling as an arrhythmogenic mechanism, dependent on Nlrp3 inflammasome activation. Our data are in keeping with previous studies of CHIP in cardiovascular disease, and further studies into the therapeutic potential of NLRP3 inhibition for individuals with TET2 CHIP may be warranted.

Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of a cancer-associated somatic mutation in white blood cells in the absence of overt hematological malignancy. It arises most commonly from loss-of-function mutations in the epigenetic regulators DNMT3A and TET2 . CHIP predisposes to both hematological malignancies and atherosclerotic cardiovascular disease in humans. Here we demonstrate that loss of Dnmt3a in myeloid cells increased murine atherosclerosis to a similar degree as previously seen with loss of Tet2 . Loss of Dnmt3a enhanced inflammation in macrophages in vitro and generated a distinct adventitial macrophage population in vivo which merges a resident macrophage profile with an inflammatory cytokine signature. These changes surprisingly phenocopy the effect of loss of Tet2 . Our results identify a common pathway promoting heightened innate immune cell activation with loss of either gene, providing a biological basis for the excess atherosclerotic disease burden in carriers of these two most prevalent CHIP mutations.

BACKGROUND AND AIMS:Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart failure. This study aimed to test the association of CHIP with new-onset arrhythmias.METHODS:UK Biobank participants without prevalent arrhythmias were included. Co-primary study outcomes were supraventricular arrhythmias, bradyarrhythmias, and ventricular arrhythmias. Secondary outcomes were cardiac arrest, atrial fibrillation, and any arrhythmia. Associations of any CHIP [variant allele fraction (VAF) ≥ 2%], large CHIP (VAF ≥10%), and gene-specific CHIP subtypes with incident arrhythmias were evaluated using multivariable-adjusted Cox regression. Associations of CHIP with myocardial interstitial fibrosis [T1 measured using cardiac magnetic resonance (CMR)] were also tested.RESULTS:This study included 410 702 participants [CHIP: n = 13 892 (3.4%); large CHIP: n = 9191 (2.2%)]. Any and large CHIP were associated with multi-variable-adjusted hazard ratios of 1.11 [95% confidence interval (CI) 1.04-1.18; P = .001] and 1.13 (95% CI 1.05-1.22; P = .001) for supraventricular arrhythmias, 1.09 (95% CI 1.01-1.19; P = .031) and 1.13 (95% CI 1.03-1.25; P = .011) for bradyarrhythmias, and 1.16 (95% CI, 1.00-1.34; P = .049) and 1.22 (95% CI 1.03-1.45; P = .021) for ventricular arrhythmias, respectively. Associations were independent of coronary artery disease and heart failure. Associations were also heterogeneous across arrhythmia subtypes and strongest for cardiac arrest. Gene-specific analyses revealed an increased risk of arrhythmias across driver genes other than DNMT3A. Large CHIP was associated with 1.31-fold odds (95% CI 1.07-1.59; P = .009) of being in the top quintile of myocardial fibrosis by CMR.CONCLUSIONS:CHIP may represent a novel risk factor for incident arrhythmias, indicating a potential target for modulation towards arrhythmia prevention and treatment.

Chronic liver disease is a major public health burden worldwide. Despite various liver injury mechanisms, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis. We examined the association between clonal hematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 58,358 individuals from four prospective cohorts with whole exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent chronic liver disease (OR 2.70 CI 1.42, 5.16, p=0.002) and incident chronic liver disease (HR 2.01 CI 1.46, 2.79, p=0.001) from both alcoholic and nonalcoholic causes. Individuals with CHIP showed 75% greater odds of MRI detectable liver inflammation and fibrosis (5.9% versus 3.5%, p=0.007) compared to those without CHIP. To assess causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (OR 2.37 CI 1.57, 3.6, p<0.001). In a dietary model of nonalcoholic steatohepatitis (NASH), mice transplanted with Tet2-deficient hematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated via NLRP3 inflammasome and increased downstream inflammatory cytokine expression, including IL6. In summary, clonal hematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression via an aberrant inflammatory response.

Background: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart failure. Whether CHIP independently predicts new-onset arrhythmias is unknown. Methods: UK Biobank participants without prevalent arrhythmias were included. Co-primary study outcomes were supraventricular arrhythmias, bradyarrhythmias, and ventricular arrhythmias. Secondary outcomes were cardiac arrest, atrial fibrillation, and any arrhythmia. Associations of any CHIP (variant allele fraction [VAF] ≥2%), large CHIP (VAF ≥10%) and gene-specific CHIP subtypes with incident arrhythmias were tested using multivariable-adjusted Cox regression. Associations of CHIP with myocardial interstitial fibrosis (T1 times on cardiac magnetic resonance [CMR]) were also tested. Results: This study included 410,879 participants (CHIP: n =13,901 [3.4%]; large CHIP: n =9,197 [2.2%]). Any and large CHIP were associated with adjusted HRs of 1.11 (95%CI, 1.04-1.18; P <0.001) and 1.14 (95%CI, 1.05-1.22; P <0.001) for supraventricular arrhythmias, 1.09 (95%CI, 1.01-1.19; P =0.029) and 1.13 (95%CI, 1.03-1.25; P =0.011) for bradyarrhythmias, and 1.15 (95%CI, 1.00-1.33; P =0.054) and 1.22 (95%CI, 1.03-1.45; P =0.023) for ventricular arrhythmias, respectively. Associations were independent of coronary artery disease and heart failure. Associations were also heterogeneous across arrhythmia subtypes and strongest for cardiac arrest. Gene-specific analyses revealed increased risk of arrhythmias across mutations in driver genes other than DNMT3A ( Figure ) . Large CHIP was associated with 1.30-fold odds (95%CI, 1.07-1.59; P =0.009) of being in the top quintile of myocardial fibrosis by CMR. Conclusions: CHIP may represent a novel risk factor for incident arrhythmias, indicating a potential target for modulation toward arrhythmia prevention and treatment. 1

Clonal hematopoiesis of indeterminate potential (CHIP) is a state in which somatic mutations in hematopoietic stem cells lead to clonal expansion of blood cells in individuals without hematologic malignancy. The mutated genes, including TET2, DNMT3A, ASXL1, TP53, JAK2, and SF3B1, are also recurrently mutated in myeloid malignancies. Individuals with CHIP have an increased risk of developing a hematologic cancer. Moreover, individuals with CHIP have an elevated risk of all-cause mortality that is significantly attributable to cardiovascular disease, independent of traditional risk factors. The mechanism for this increased risk is likely linked to increased inflammation driven by mutated macrophages, in part through inflammasome activation. This has broadened our understanding of how chronic diseases are influenced by CHIP and of the mechanistic role of inflammation in these disorders.

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is a phenomenon where hematopoietic stem cells acquire leukemogenic mutations without blood cancer. CHIP is a causal risk factor for coronary artery disease (CAD), yet underlying mechanisms remain unclear. The plasma proteome may provide novel mechanistic insights into the links between CHIP and CAD. Methods: We studied the associations of CHIP with the plasma proteins and CAD risk in four Trans-Omics for Precision Medicine (TOPMed) longitudinal cohorts: ARIC (N=9,084), CHS (N=1,727), JHS (N=1,858), and MESA (N=978). CHIP (variant allele fraction >2%) was identified from whole genome sequences of blood DNA and modeled both as a composite of the most common drivers ( DNMT3A , TET2 , ASXL1 , and JAK2 ) and separately. Levels of ~1,300 serum proteins measured by SomaScan were log-transformed and residualized on study-specific covariates. The association between CHIP and protein levels was estimated across all participants within each study, as well as by sex, and meta-analyzed. For proteins significantly (FDR<0.05) associated with CHIP, pathway analysis and functional validation in Tet2-/- mice were conducted. Results: Across all studies (mean age: 59.8 y; 43.6% male), 720 (5.6%) individuals were identified with CHIP. There were 143 significant CHIP-protein pairs, with carbonic anhydrase 1, lysozyme C, and properdin being the most associated proteins. TET2 had the largest number of, and strongest, associations among examined driver genes. In sex-stratified analysis, follicle-stimulating hormone was inversely associated in females. Pathway analysis implicated the inflammation-related STAT3 and IL-17 signaling pathways. We observed significantly greater expression of Cfp and Lyz (encoding properdin and lysosome C, respectively) in the monocytes of Tet2 -/- female mice compared to wild-type female mice and Tet2 -/- male mice. A number of proteins (including PCSK9) were significantly associated with both CHIP and CAD, suggesting both shared and nonshared mechanisms. Conclusions: CHIP, particularly TET2 , is broadly associated with plasma proteins, as validated by evidence in Tet2-/- mice. Further studies are needed to understand the biological mechanisms linking CHIP to CAD.

Targeted protein degradation is a rapidly advancing and expanding therapeutic approach. Drugs that degrade GSPT1 via the CRL4CRBN ubiquitin ligase are a new class of cancer therapy in active clinical development with evidence of activity against acute myeloid leukemia in early-phase trials. However, other than activation of the integrated stress response, the downstream effects of GSPT1 degradation leading to cell death are largely undefined, and no murine models are available to study these agents. We identified the domains of GSPT1 essential for cell survival and show that GSPT1 degradation leads to impaired translation termination, activation of the integrated stress response pathway, and TP53-independent cell death. CRISPR/Cas9 screens implicated decreased translation initiation as protective following GSPT1 degradation, suggesting that cells with higher levels of translation are more susceptible to the effects of GSPT1 degradation. We defined 2 Crbn amino acids that prevent Gspt1 degradation in mice, generated a knockin mouse with alteration of these residues, and demonstrated the efficacy of GSPT1-degrading drugs in vivo with relative sparing of numbers and function of long-term hematopoietic stem cells. Our results provide a mechanistic basis for the use of GSPT1 degraders for the treatment of cancer, including TP53-mutant acute myeloid leukemia.

Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory cytokines, including interleukin-1 beta (IL-1 beta). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1 beta, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177 824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] >= 2%: odds ratio [OR], 1.69; 95% CI, 1.09-2.61; P = .0189; UKB, CHIP with VAF >= 10%: OR, 1.25; 95% CI, 1.05-1.50; P = .0133). Moreover, individuals with CHIP and a VAF >= 10% had an increased risk of incident gout (UKB: hazard ratio [HR], 1.28; 95% CI, 1.06-1.55; P = .0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1 beta secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1 beta in response to MSU crystals in vitro, which was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1 beta levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in patients with gout.

Abstract Background: Gout is a highly prevalent arthritis associated with debilitating joint pain and functional impairment. It is caused by elevated serum uric acid levels (hyperuricemia) and triggered by precipitation of urate crystals in and around joints. Urate crystals are ingested by macrophages and provoke an innate immune response with subsequent secretion of inflammatory cytokines including interleukin 1 beta (IL-1B). Clonal hematopoiesis of indeterminate potential (CHIP) is a precursor to hematologic malignancies defined by somatic mutations in hematopoietic cells that drive clonal expansion and inflammation. Specifically, CHIP is associated with an increased risk of cardiovascular events and can accelerate atherosclerosis. Mutations in TET2, one of the most commonly mutated genes in CHIP, lead to increased expression of IL-1B through inflammasome activation. Here we investigate the role of CHIP in the development of gout using a combination of human genetic studies and mouse models of CHIP. Methods: To determine the clinical association between CHIP and gout, we analyzed exome sequencing and clinical data from >50,000 individuals included in the UK Biobank (UKB) and Mass General Brigham Biobank (MGBB). To test whether mutant blood cells can promote gout, Tet2- and Dnmt3a-deficient mouse models were used. Results: CHIP was more prevalent in individuals with gout than without gout (MGBB: 12.3% vs. 7.9%, P=0.017; UKB: 8.2% vs. 5.8%, P=0.011) and individuals with CHIP were at increased risk of developing gout (UKB: hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.27-2.00; P<0.001). In multivariable analyses, CHIP with variant allele fraction (VAF) ≥10% was associated with higher risk of incident gout compared to no CHIP after adjusting for common gout risk factors (UKB: HR, 1.46; 95% CI, 1.07-2.01; P=0.019). To determine if somatically mutated blood cells directly contribute to the aberrant immune response in gout, we utilized a mouse model of MSU-mediated peritonitis. Compared to control animals, mice with hematopoietic-specific Tet2 deficiency demonstrated markedly increased IL-1B serum levels after injection with MSU (P<0.05). To study gene-specific contributions to joint tissue injury, we established an in vivo model that closely represents the clinical phenotype of gout. Following MSU treatment in situ, Tet2-deficient animals developed exacerbated paw edema compared to wild-type controls (P<0.05). We next generated bone-marrow derived macrophages (BMDM) from Tet2- and Dnmt3a-deficient mice to specifically investigate the MSU-induced cytokine profile in mutant macrophages. Consistent with our in vivo data, IL-1B was the most differentially secreted cytokine after MSU treatment in both Tet2-deficient and Dnmt3a-deficient BMDM compared to wild-type cells (P<0.05). RNA-sequencing confirmed a strong pro-inflammatory gene expression signature of MSU-treated Tet2- and Dnmt3a-deficient macrophages. Finally, we found that pharmacologic inhibition or genetic loss of inflammasome abrogated IL-1B secretion in Tet2- and Dnmt3a-deficient macrophages treated with MSU. Conclusion: CHIP is associated with an increased risk of having and developing gout in human cohorts and distinct mouse models confirm a direct influence of mutant hematopoietic cells on gout-induced inflammation and arthropathy. CHIP may provide a mechanistic explanation for the heterogeneity in clinical symptoms and inflammation due to gout. Our findings substantiate the biologic rationale for interventional strategies directed at CHIP-associated inflammatory conditions beyond cardiovascular disease and thereby define a path for clinical evaluation of targeted therapies for patients with CHIP-positive gout. Disclosures Miller: Foundation Medicine: Consultancy. Neuberg: Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Other: Stock ownership. Natarajan: Amgen: Research Funding; Apple: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Boston Scientific: Research Funding; Blackstone Life Sciences: Consultancy; Genentech: Consultancy; Foresite Labs: Consultancy. Rao: Janssen: Honoraria, Research Funding; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Merck: Honoraria; Scipher Medicine: Honoraria.

Osteoporosis is caused by an imbalance of osteoclasts and osteoblasts, occurring in close proximity to hematopoietic cells in the bone marrow. Recurrent somatic mutations that lead to an expanded population of mutant blood cells is termed clonal hematopoiesis of indeterminate potential (CHIP). Analyzing exome sequencing data from the UK Biobank, we found CHIP to be associated with increased incident osteoporosis diagnoses and decreased bone mineral density. In murine models, hematopoietic-specific mutations in Dnmt3a, the most commonly mutated gene in CHIP, decreased bone mass via increased osteoclastogenesis. Dnmt3a−/− demethylation opened chromatin and altered activity of inflammatory transcription factors. Bone loss was driven by proinflammatory cytokines, including Irf3-NF-κB–mediated IL-20 expression from Dnmt3a mutant macrophages. Increased osteoclastogenesis due to the Dnmt3a mutations was ameliorated by alendronate or IL-20 neutralization. These results demonstrate a novel source of osteoporosis-inducing inflammation.

Importance Despite current standards of cardiovascular care, a considerable residual burden of risk remains in both primary and secondary prevention. Clonal hematopoiesis of indeterminate potential (CHIP) has recently emerged as a common, potent, age-associated, independent risk factor for myocardial infarction, stroke, heart failure events, and survival following percutaneous aortic valve intervention. The presence of CHIP results from the acquisition of somatic mutations in a small number of leukemia driver genes found in bone marrow stem cells, leading to the expansion of leukocytes clones in peripheral blood. The association between CHIP and cardiovascular disease likely involves activation of the inflammasome pathway. More common DNA sequencing identifies individuals with CHIP who then seek advice regarding management of their cardiovascular risk. Observations Using clinical vignettes based on real encounters, we highlight some of the diverse presentations of CHIP, ranging from incidental identification to that detected during cancer care, that have brought patients to the attention of cardiovascular practitioners. We illustrate how we have applied a consensus-based approach to the evaluation and management of cardiovascular risk in specific patients with CHIP. Since we currently lack evidence to guide the management of these individuals, we must rely on expert opinion while awaiting data to furnish a firmer foundation for our recommendations. Conclusions and Relevance These vignettes illustrate that the management of CHIP should involve an individualized plan based on features such as comorbidities, life expectancy, and other traditional cardiovascular risk factors. Because individuals with CHIP will increasingly seek advice from cardiovascular specialists regarding management, these examples provide a template for approaches based on a multidisciplinary perspective. The current need for reliance on expert opinion illustrates a great need for further investigation into the management of this newly recognized contributor to residual cardiovascular risk, both in patients who are apparently well and those with established cardiovascular or malignant disease.

A Correction to this paper has been published: https://doi.org/10.1038/s41586-021-03280-1.