Page 16 - GTM-4-3

Global Translational Medicine Inflammation in CVD: Mechanisms and markers

4. IL-6 inhibition in cardiac disease 4.3. Integrative inflammatory networks in ASCVD
and chronic kidney disease (CKD): While each inflammatory pathway contributes uniquely
A multidimensional perspective to atherogenesis, their interactions form a tightly
interconnected network that amplifies vascular injury
4.1. Introduction to IL-6 signaling and plaque progression. IL-1 signaling, often triggered by
IL-6 is pivotal in immune regulation and inflammatory necrotic cell death or inflammasome activation, initiates
responses, acting through complex signaling pathways. It a cascade that upregulates IL-6, bridging local tissue
is secreted by various cell types, including macrophages, inflammation with systemic responses, such as hepatic
fibroblasts, and endothelial cells, often in response to hs-CRP production. IL-6, in turn, reinforces monocyte
upstream stimuli, such as IL-1 or tissue injury. IL-6 signals activation and endothelial dysfunction, enhancing the
through three distinct mechanisms: (i) classic signaling, in expression of adhesion molecules and facilitating leukocyte
which IL-6 binds to membrane-bound IL-6 receptors and infiltration. Concurrently, SGK1 intensifies this pro-
activates glycoprotein 130 (gp130); (ii) trans-signaling, inflammatory signaling environment by promoting NF-κB
which uses soluble IL-6 receptors to broaden its effect to activity and NLRP3 inflammasome assembly, further
cells lacking IL-6 receptors; and (iii) trans-presentation, a increasing IL-1β and IL-6 production. CD47 exacerbates
specialized process involving dendritic cells and T cells. this cycle by impairing efferocytosis, allowing apoptotic
16
All signaling modes converge on gp130 and activate the cells and inflammatory debris to accumulate within
Janus kinase signal transducer and activator of transcription the plaque, thereby sustaining immune cell activation.
(JAK-STAT) pathway, driving gene expression changes In addition, MPO and Lp-PLA2 perpetuate oxidative
that promote inflammation, endothelial dysfunction, and stress, leading to destabilized plaques and amplified
disease progression. Beyond its mechanistic roles, IL-6 has cytokine release. These interwoven pathways collectively
emerged as a potent clinical biomarker and therapeutic fuel a feed-forward loop of inflammation, oxidative
target in inflammation-driven CVD. Elevated IL-6 levels injury, and immune dysregulation – underpinning the
are independently associated with adverse outcomes in pathophysiology of plaque instability and thrombotic
coronary artery disease, heart failure, and CKD, even after events in ASCVD.
adjusting for traditional risk markers. Genetic evidence
supports a causal relationship between IL-6 signaling and The downstream consequences of these overlapping
ASCVD, while post hoc analyses from the CANTOS trial inflammatory circuits become especially pronounced in
demonstrated that a reduction in IL-6 levels was closely chronic cardiovascular and renal conditions, where IL-6
tied to improved cardiovascular outcomes. These insights drives maladaptive tissue remodeling, systemic immune
16
have led to the development of IL-6-targeted therapies, activation, and end-organ dysfunction – hallmarks of both
such as ziltivekimab, which is currently being tested in heart failure and CKD.
the ZEUS trial (ClinicalTrials.gov ID: NCT05021835) to 4.4. The role of IL-6 in heart failure
reduce cardiovascular events in patients with CKD and
elevated inflammatory risk. IL-6 plays a central role in heart failure, promoting adverse
cardiac remodeling through inflammatory pathways.
4.2. The role of IL-6 in acute coronary ischemia Elevated IL-6 levels have been consistently associated with
Acute coronary ischemia, characterized by myocardial higher rates of hospitalization, cardiovascular mortality,
hypoxia and plaque rupture, is significantly affected by and worsening cardiac function. Findings from the
elevated IL-6 levels, which amplify systemic and local BIOSTAT-CHF study revealed that IL-6 correlated with
inflammation. In phase II trials, including the ASSAIL-MI markers of disease severity, including elevated N-terminal
and SOLID-TIMI 52 studies, a single administration of pro-B-type natriuretic peptide and cardiac fibrosis. 16,17
17
the IL-6 receptor antagonist tocilizumab in patients with Moreover, IL-6 stimulates hepcidin production,
ST-segment elevation myocardial infarction demonstrated contributing to anemia – a common exacerbating factor in
reductions in microvascular obstruction and inflammatory heart failure. 16,17 Clinical evidence from the CANTOS trial
markers, such as CRP. These improvements were evident demonstrated that patients with the highest reductions in
during hospitalization and were particularly notable when IL-6 following anti-inflammatory therapy exhibited the
treatment was initiated after a delay of more than 3 h from most significant declines in heart failure hospitalizations.
symptom onset. Mechanistically, IL-6 inhibition mitigates 4.5. The role of IL-6 in CKD and hemodialysis
the acute-phase response by decreasing monocyte
chemoattraction and neutrophil activation, thereby Patients with CKD and those undergoing hemodialysis
limiting inflammatory damage to myocardial tissue. experience elevated IL-6 levels due to persistent oxidative

Volume 4 Issue 3 (2025) 8 doi: 10.36922/GTM025100023