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Global Translational Medicine Inflammation in CVD: Mechanisms and markers

stress, tissue hypoxia, and retention of uremic toxins. 16,17 pathways through distinct mechanisms. TET2 mutations
IL-6 predicts vascular events and mortality more accurately lead to the loss of its demethylase function, increasing
than traditional lipid measures in prognostic accuracy. histone acetylation at inflammatory gene promoters, such
Elevated IL-6 levels contribute to systemic inflammation, as those in IL1B and NLRP3. Tet2-deficient macrophages
exacerbating endothelial dysfunction and promoting display enhanced inflammasome priming and IL-1β
atherosclerosis. In hemodialysis patients, IL-6 also affects production in response to oxidized LDL and other
anemia by modulating hepcidin levels, reducing iron danger signals. 18-20 Treatment with NLRP3 inhibitors
bioavailability, and impairing erythropoiesis. 16,17 Data in murine Tet2-CHIP models significantly attenuates
from the CANTOS trial and related studies suggest that plaque burden, underscoring the therapeutic potential of
targeting IL-6 pathways reduces inflammatory marker targeting upstream inflammatory pathways. DNMT3A
expression and may improve cardiovascular outcomes in mutations, while impairing epigenetic regulation, alter
CKD patients. gene expression through distinct methylation patterns.
Although they similarly skew hematopoiesis and promote
5. Clonal hematopoiesis as a risk factor for a pro-inflammatory macrophage phenotype, DNMT3A-
ASCVD mutant cells show increased IL-6 and chemokine secretion

5.1. Clonal hematopoiesis of indeterminate with relatively less IL-1β production, suggesting partial
potential (CHIP) and atherosclerosis divergence from Tet methylcytosine dioxygenase 2 (Tet2)-
mediated pathways. 18-20 JAK2 V617F mutation, a gain-of-
CHIP is characterized by somatic mutations in hematopoietic function mutation, enhances cytokine signaling through
stem and progenitor cells (HSPCs), increasingly recognized as STAT pathways and drives NLRP3 and AIM2 inflammasome
a key contributor to ASCVD. Frequently observed mutations activation. Jak2-mutant macrophages demonstrate
– most commonly in TET2, DNMT3A, ASXL1, and JAK2 – metabolic reprogramming – elevated glycolysis and
promote myeloid-biased differentiation and endow HSPCs mitochondrial reactive oxygen species production – that
with enhanced self-renewal and inflammatory potential. promotes pyroptosis and plaque instability. 18-20 In contrast
These mutations are not merely passenger events. They to TET2, AIM2 appears to play a more dominant role in
induce functional changes in immune cells that accelerate JAK2-associated atherogenesis. DNA damage response
atherosclerosis. In murine models, the transplantation of Tet2- gene mutations, such as TP53 and PPM1D, also contribute
deficient bone marrow promotes plaque growth, enhanced by expanding inflammatory myeloid populations, though
macrophage accumulation, and increased IL-1β secretion, without consistent inflammasome activation, suggesting
mainly through NLRP3 inflammasome activation, even when inflammasome-independent contributions to plaque
present in only 10% of donor marrow. 18-20 This indicates that growth. 18-20 Collectively, these mutation-specific pathways
minor clonal populations can exert outsized inflammatory point to a nuanced immunoepigenetic landscape and
effects. Similarly, Jak2 V617F mutation increases monocyte support the development of tailored anti-inflammatory
recruitment, macrophage proliferation, and necrotic core
formation in plaques, driven by dual activation of AIM2 therapies targeting CHIP-associated atherosclerosis.
and NLRP3 inflammasomes. CHIP-mutant macrophages 6. Conclusion
exhibit a hyperinflammatory phenotype that compromises
efferocytosis, destabilizes plaques, and enhances leukocyte Inflammation drives ASCVD through complex immune
recruitment. These effects are not limited to atherosclerosis pathways, including cytokine signalings, inflammasome
alone but extend to impaired cardiac repair and increased activation, and clonal hematopoiesis. Biomarkers such as
fibrosis in heart failure models. Epidemiologically, CHIP hs-CRP, IL-1, IL-6, and MPO, as well as emerging targets
carriers – especially those with high variant allele fractions such as CD47 and SGK1, provide critical insights into
– face a twofold increased risk of ASCVD, comparable to disease progression and risk stratification. Understanding
traditional risk factors and independent of lipid levels or these mechanisms refines our ability to predict
smoking history. 18-20 Emerging evidence also links CHIP cardiovascular events and uncover novel pathogenic
to epigenetic aging, suggesting an additional biomarker pathways. Future research should focus on integrating these
framework for risk stratification. biomarkers to enhance diagnostic precision and deepen
our understanding of inflammatory drivers in CVD. As
5.2. Gene variants associated with clonal the first part of a two-part review, this article outlines the
hematopoiesis of indeterminate potential immunopathogenic mechanisms and biomarker landscape
The pathogenicity of CHIP is highly dependent on the of inflammation in CVD, while Part II will focus on
specific mutated gene, each of which affects inflammatory therapeutic strategies targeting inflammatory pathways.

Volume 4 Issue 3 (2025) 9 doi: 10.36922/GTM025100023