Review Article
Clonal hematopoiesis and circulating biomarkers in cardiovascular diseases
2026 年 72 巻 4 号 p. 289-294
詳細
2026 年 72 巻 4 号 p. 289-294
Clonal hematopoiesis, characterized by the age-related expansion of hematopoietic stem cell clones harboring somatic mutations, has emerged as an essential contributor to cardiovascular disease. Accumulating evidence indicates that clonal hematopoiesis driven by myeloproliferative neoplasm-associated driver mutations, particularly JAK2, is associated with an increased risk of vascular and cardiac complications, even at low variant allele frequencies. Experimental models and clinical studies demonstrate that mutant hematopoietic cells promote inflammation and pathological remodeling, thereby contributing to cardiovascular disorders such as pulmonary hypertension and aortic aneurysm. In addition, advances in circulating biomarker research have enabled less invasive assessment of cardiovascular diseases. Biomarkers, including cell-free DNA, reflect ongoing cardiac damage, while the extracellular matrix protein of collagen triple helix repeat-containing protein 1 (CTHRC1) provides insights into cardiac fibrosis. Clonal hematopoiesis and circulating biomarkers may enhance risk stratification and improve mechanistic understanding of cardiovascular pathology. This review summarizes current evidence of clonal hematopoiesis and circulating biomarkers in cardiovascular diseases.
Cardiovascular disease is the leading cause of mortality worldwide;however, a substantial proportion of cardiovascular risk cannot be fully explained by traditional risk factors. Despite advances in lipid-lowering, antihypertensive, and antithrombotic therapies, residual cardiovascular risk persists, highlighting the need to identify disease mechanisms1). In recent years, clonal hematopoiesis of indeterminate potential (CHIP), characterized by age-related expansion of hematopoietic stem cell clones harboring somatic mutations in the absence of overt hematologic malignancy, has emerged as a novel contributor to cardiovascular disease2). CHIP is detected in more than about 10% of individuals over 70 years of age and increases in prevalence with aging, making it highly relevant to the aging cardiovascular population3,4).
Epidemiological studies have demonstrated that CHIP is associated with increased risks of atherosclerosis, heart failure, and cardiovascular mortality3,4). Importantly, these associations are independent of traditional cardiovascular risk factors, suggesting that CHIP represents a distinct biological driver of cardiovascular disease4). Mechanistically, CHIP is increasingly recognized as a chronic inflammatory condition in which mutant hematopoietic cells give rise to dysfunctional immune cells that contribute to vascular and myocardial injury5,6).
Among CHIP-associated mutations, myeloproliferative neoplasm-related driver mutations, particularly JAK2V617F, are associated with cardiovascular complications3,7). Experimental and clinical studies indicate that mutant hematopoietic cells promote chronic inflammation through aberrant cytokine signaling and immune cell activation, thereby accelerating atherosclerosis, pulmonary hypertension, and myocardial injury8-10). These findings suggest that clonal hematopoiesis acts as an upstream inflammatory driver of cardiovascular disease, linking aging, inflammation, and cardiovascular risk factors.
Advances in circulating biomarker research have enabled less invasive and more sensitive assessment of cardiovascular injury and remodeling11,12). While conventional biomarkers such as natriuretic peptides and cardiac troponins primarily reflect hemodynamic stress or cardiac injury, emerging biomarkers provide complementary biological information related to inflammation, fibrosis, and cell death13-15). Circulating cell-free DNA offers a direct molecular readout of ongoing cardiomyocyte death, whereas extracellular matrix proteins reflect myocardial fibrosis and structural remodeling. Clonal hematopoiesis and circulating biomarkers may enhance cardiovascular risk stratification and improve the mechanistic understanding of cardiovascular disorders.
Among myeloproliferative neoplasm driver mutations, JAK2V617F has the strongest association with cardiovascular complications. Large population-based studies and disease-specific cohorts consistently demonstrate an increased incidence of arterial thrombosis, heart failure, and vascular disease in individuals harboring JAK2V617F4,16). Our clinical studies have shown that low-level JAK2V617F-mediated clonal hematopoiesis is significantly more prevalent in patients with vascular disease and is independently associated with cardiovascular events17). Importantly, these associations persist after adjustment for conventional risk factors and are accompanied by increased interleukin-1β expression, supporting a central role of inflammation17).
Patients with myeloproliferative neoplasms of JAK2V617F have a risk for the development of aortic aneurysms18,19). We provided mechanistic insights by murine bone marrow transplantation and abdominal aortic aneurysm models, in which hematopoietic JAK2V617F accelerates angiotensin II-induced abdominal aortic aneurysm formation in mice19-21). In this model, JAK2V617F-positive bone marrow-derived macrophages and neutrophils infiltrate into the vascular wall, activate STAT3 signaling, and upregulate matrix metalloproteinases, thereby degrading the elastic lamina and promoting abdominal aneurysm progression (Figure 1). Pharmacological inhibition of JAK2 signaling with ruxolitinib attenuates these vascular changes, reducing the incidence of abdominal aortic aneurysm rupture and improving survival in this model19). These findings establish a causal role for mutant hematopoietic cells in aneurysm pathogenesis and suggest potential therapeutic implications beyond hematologic disease.
In addition to JAK2 and CALR mutations, DNMT3A and TET2 are the most common mutations in CHIP. DNMT3A and TET2 mutations have been related to cardiovascular disease through enhanced inflammatory signaling22).
Hematopoietic JAK2V617F-positive cells for the development of aortic aneurysm
Bone marrow-derived JAK2V617F-positive macrophages and neutrophils infiltrate around the abdominal aortic aneurysm. These inflammatory cell infiltrations activate STAT3 signaling and increase matrix metalloproteinase (MMP) expression, thereby promoting elastic lamina degradation and aneurysm progression.
CALR frameshift mutations, another myeloproliferative neoplasm driver mutation, have also been implicated in cardiovascular complications. Pulmonary hypertension is a recognized but poorly understood complication of myeloproliferative neoplasms23,24). To elucidate the underlying mechanisms, we utilized mice harboring CALR exon 9 frameshift mutations that present features of the myeloproliferative neoplasm phenotype25). Experimental models of bone marrow transplantation using these mice with mutant CALR demonstrate exacerbated pulmonary hypertension in response to chronic hypoxia25). This phenotype is mediated by bone marrow-derived mutant CALR-positive macrophages, emphasizing the importance of hematopoietic-immune crosstalk. Mutant CALR-positive macrophages exhibit enhanced STAT3 activation and increased endothelin-1 expression, promoting pulmonary vascular remodeling (Figure 2). These findings provide direct evidence that mutant hematopoietic cells can drive pulmonary vascular disease through inflammatory mechanisms, independent of thrombosis25,26). Together with data on JAK2V617F, these studies broaden the cardiovascular spectrum of clonal hematopoiesis-associated disease.
Hematopoietic mutant CALR-positive cells for the development of pulmonary hypertension
Bone marrow-derived mutant CALR-positive macrophages infiltrate around the pulmonary artery and increase endothelin-1 expression and enhance STAT3 signaling, leading to vascular remodeling and pulmonary hypertension.
While clonal hematopoiesis promotes cardiovascular injury, circulating biomarkers provide insight into its downstream consequences11,12,27,28). Cell-free DNA has emerged as a biomarker reflecting ongoing tissue damage29). Using methylation-based digital polymerase chain reaction, cardiomyocyte-specific cell-free DNA can be detected in circulation and is significantly elevated in patients with heart failure30). Cardiomyocyte-specific cell-free DNA correlates with cardiac troponin levels but not with natriuretic peptides, suggesting that cell-free DNA reflects active cardiomyocyte death rather than hemodynamic stress. This approach provides a direct molecular readout of myocardial injury and may be particularly useful for monitoring disease activity.
Extracellular matrix remodeling is a hallmark of advanced cardiovascular disease. Right ventricular dysfunction is a leading cause of death in patients with pulmonary arterial hypertension11,31-33). Collagen triple helix repeat-containing protein 1 (CTHRC1) has been identified as a circulating biomarker associated with right ventricular dysfunction and fibrosis in pulmonary hypertension34). CTHRC1 expression is increased in the fibrosis area of the right ventricle from monocrotaline-induced pulmonary hypertension in rats. Elevated plasma CTHRC1 levels correlate with right ventricular dysfunction in patients with pulmonary hypertension. CTHRC1 levels also decrease following effective interventional treatment, associated with improved hemodynamics in patients with chronic thromboembolic pulmonary hypertension35). These findings indicate that CTHRC1 is a biomarker of hemodynamics, fibrosis, and disease severity34).
Integrating CHIP with circulating biomarker profiling may provide synergistic risk stratification. Although direct clinical data remain limited, CHIP-associated inflammatory activation may enhance cardiomyocyte injury and extracellular matrix remodeling, which could be captured by circulating biomarkers. Future research should focus on integrating genomic information on clonal hematopoiesis with circulating biomarker profiling to enable refined cardiovascular risk stratification and precision medicine. While JAK2 inhibition attenuates vascular pathology in experimental models, routine pharmacologic treatment in individuals with low-allele-burden CHIP is not currently justified. Future clinical trials are required to determine whether targeted mutation-specific therapies can reduce cardiovascular risk in carriers of CHIP.
These studies support the notion that clonal hematopoiesis—particularly myeloproliferative neoplasm driver mutations—acts as an upstream driver of cardiovascular disease through inflammatory immune cell infiltration. Circulating biomarkers, such as cell-free DNA and CTHRC1, capture downstream processes, including cardiomyocyte death, hemodynamic stress, and myocardial fibrosis, providing complementary tools for mechanistic insight and clinical risk assessment.
The authors would like to thank all those who contributed to these studies. Figures were created in BioRender.
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