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Modifiable Environmental and Lifestyle Factors Converge on the NLRP3–Caspase-1 Axis to Accelerate Aortic Aneurysm Progression: Mechanisms, Multi-Omics Gaps, and Therapeutic Implications

Submitted:

16 September 2026

Posted:

23 September 2026

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Abstract
No drug has yet been shown to stop an aortic aneurysm (AA, abdominal AAA or thoracic TAA) from enlarging, and many patients are recognised only once the wall is already failing. Alongside the classical risk factors, three conditions that patients and clinicians can actually change—chronic cold exposure, lack of exercise and severe infection—have each been tied to faster progression, although their molecular overlap is rarely discussed together. This narrative review draws on 80 sources from PubMed, Web of Science and CNKI (2003–2026). Upstream the three insults look quite different: cold acts through extracellular cold-inducible RNA-binding protein (eCIRP)–TLR4 signalling and the sympathetic nervous system, inactivity through low and oscillatory wall shear stress, and infection through pathogen-associated molecular patterns. Downstream they meet on NF-κB, MMP-2/9, oxidative stress and loss of vascular smooth muscle cells, with the NLRP3 inflammasome as the shared bottleneck—its caspase-1 both releases IL-1β/IL-18 and cleaves pro-MMP-9 directly. We use this convergence to re-read the still piecemeal single-omics evidence and weigh NLRP3-, IL-1β- and CIRP-directed drugs against exercise, warmth and vaccination. The clearest gaps are multifactorial models, paired multi-omics cohorts and trials that follow expansion rate.
Keywords: 
aortic aneurysm
;  
cold exposure
;  
cold-inducible RNA-binding protein
;  
physical inactivity
;  
wall shear stress
;  
NLRP3 inflammasome
;  
matrix metalloproteinase 9
Subject: 
Medicine and Pharmacology  -   Cardiac and Cardiovascular Systems

1. Introduction

Aortic aneurysm is a permanent, focal dilatation of a weakened wall, named abdominal (AAA) or thoracic (TAA) by its location. Roughly 4%–7% of men over 65 carry an AAA, and aneurysm disease kills about 200,000 people each year 1. It is usually silent, so a sizeable minority first present with rupture, which kills more than 80% of those affected 2. Open or endovascular repair is still the only treatment that clearly works; no drug has been shown to slow expansion 1,2. The familiar risks are age, male sex, smoking, hypertension, atherosclerosis and inherited connective-tissue disease, and the occasional coexistence of AAA with abdominal-wall hernia hints at an inborn weakness of the wall 3.
Three modifiable exposures have had less attention than they deserve. Cold is one. Time-stratified case-crossover work from northeast China, Japan and the United States all tie low temperature to dissection and rupture 4,5,6. Sedentary living is another: cohort and meta-analytic evidence links habitual activity and fitness to a lower chance of AAA 7. Infection is the third, whether as direct bacterial invasion of the wall (an infected or “mycotic” aneurysm) or as sepsis that speeds an existing aneurysm along 8–10. In real life these overlap. Winter brings cold and respiratory infection at the same time, and the endothelial and metabolic fallout of inactivity leaves the wall less able to tolerate either. Our aim is to read the three together—to trace how cold, inactivity and infection accelerate aneurysm through shared inflammatory circuits, where those circuits converge, and what they mean for treatment and for the omics work still missing. We write as a narrative rather than a systematic review and make no attempt at meta-analysis.

2. A Shared Molecular Framework for Aortic Aneurysm

2.1. Chronic Inflammation, MMP-Mediated Matrix Degradation and VSMC Loss

Three processes do most of the damage—chronic inflammation, loss of extracellular matrix (ECM) and depletion of vascular smooth muscle cells (VSMCs)—and they feed one another 1,2. Macrophages, lymphocytes and neutrophils accumulate in the wall; activated macrophages release TNF-α, IL-1β, IL-6 and MCP-1, which draw in still more leukocytes and switch on proteases 1,11. IL-1β sits near the top of this cascade: engaging endothelial IL-1R1, it signals through MyD88/IRAK/TRAF to NF-κB and turns on adhesion molecules and chemokines 11. The matrix side rests on MMP-2 and MMP-9, supplied by infiltrating leukocytes and by switched VSMCs, which digest elastin and collagen whenever the balance with their tissue inhibitors tips 12. MMP-9 was long thought to need plasmin or MMP-3 to remove its propeptide. Ren and colleagues found a shortcut in mice: caspase-1 coming off the inflammasome can cleave that propeptide itself 13. One enzymatic step thus joins inflammatory sensing straight to matrix breakdown.
Healthy VSMCs are contractile, built around α-SMA, SM22α and myosin heavy chain. Inflammation, mechanical strain and oxidant stress push them toward a synthetic, secretory state that makes MMPs and cytokines while giving up contractile force, a shift that carries particular weight in TAA and dissection 14,15. scRNA-seq has since shown how varied these cells are, with pro-inflammatory, senescent and stem-like subsets side by side 16–18. In dissected tissue, LOX-high fibroblasts are over-activated through BMP signalling and secrete COL5A1, a plausible circulating marker 19. The same NLRP3–caspase-1 pathway also degrades VSMC contractile proteins and so weakens the wall mechanically 20.

2.2. The NLRP3 Inflammasome as a Convergent Amplifier

NLRP3 is a cytosolic assembly of NLRP3, ASC and caspase-1; once built, caspase-1 releases mature IL-1β and IL-18 and can drive pyroptosis 21. In aneurysm it has no shortage of triggers—oxidised LDL, cholesterol crystals, ROS, bacterial products and mechanical strain among them. That cholesterol crystals switch macrophage NLRP3 on was first shown in atherosclerosis 22, and NLRP3 particles released outside the cell can be taken back up by smooth muscle cells to keep local inflammation going 23. This breadth is why NLRP3 is useful as an organising concept: very different insults are funnelled into one stereotyped response 20,21.

3. Chronic Cold Exposure: The eCIRP–TLR4 Axis and Sympathetic Activation

3.1. Epidemiological Evidence

The pattern holds across quite different settings. A 2026 retrospective series from northeast China found that sustained cold and abrupt day-to-day falls both raised dissection risk, the effect lingering for more than a week 4. A Japanese case-crossover study then pulled two events apart: dissection tracked sudden drops whereas rupture tracked prolonged cold, a hint that the two do not share identical physiology 5. Nationwide US CDC WONDER data point the same way for mortality 6.

3.2. The CIRP–TLR4–NF-κB Axis

Cold-inducible RNA-binding protein (CIRP) is a stress protein with fingers in several cardiac and vascular processes 24,25. Cold or hypoxia moves it out of the cell as extracellular CIRP (eCIRP), where it behaves as a damage-associated molecular pattern 24. Macrophages and endothelial cells read eCIRP through TLR4-MD2 24 and through TREM-1 26; TLR4 then uses MyD88 to switch on NF-κB and the TNF-α/IL-1β/IL-6/MCP-1 programme 27,28. In BAPN-treated mice, acute cold (4 ± 1 °C) drove vascular inflammation and MMP-2 through eCIRP–TLR4 and raised dissection risk, and adding CIRP to endothelial cells reproduced the effect in vitro 27.
Li and colleagues supply the most complete AAA chain. Human AAA tissue held 5.6-fold more CIRP mRNA and 93% more CIRP protein, and serum CIRP tracked severity; in elastase-treated rats, anti-CIRP antibody (1 mg/kg) held dilatation down and cut MMP-2/9, TNF-α, MCP-1 and CD68+ infiltration; recombinant CIRP raised macrophage MMP-9 mRNA as much as 5.5-fold and migration by about 2.7-fold 29. A caveat matters: these are acute models, whereas a human aneurysm develops over years, and CIRP’s role under genuinely chronic cold is still untested.

3.3. Sympathetic Activation, Oxidative Stress and a Prothrombotic State

Cold also fires up the sympathetic nervous system. Catecholamines rise, the heart speeds, peripheral vessels clamp down, and blood pressure and platelet activity go up with them 30,31. By Laplace’s law wall tension scales with pressure times radius, so even a modest pressure rise loads an existing aneurysm more heavily. Sympathetic activation recruits renin–angiotensin too; angiotensin II generates NADPH-derived ROS and pushes VSMC switching and MMP expression 2. Oxidant production outruns antioxidant capacity and feeds NF-κB and MAPK 32. Fibrinogen can rise by as much as 23% in winter, viscosity rises, and the intraluminal thrombus that follows becomes a slow, luminal source of macrophage and neutrophil proteases 30.

4. Physical Inactivity: Disturbed Haemodynamics and Mechanotransduction

4.1. Epidemiological Evidence

Across cohorts and meta-analyses, active and fit people develop less AAA and carry a smaller burden 7,33–36. That pattern raises a mechanical question: how does a sedentary life actually reach the aortic wall?

4.2. Low and Oscillatory Wall Shear Stress

Wall shear stress (WSS), the friction of flowing blood on the endothelium, is a major homeostatic cue; healthy aortic WSS runs around 1–7 Pa in one direction. A weak leg-muscle pump slows distal flow and leaves the infrarenal aorta bathed in low (<0.4 Pa), oscillating shear 37,38. Dalman’s group tested the consequence in elastase-treated rats, pairing an arteriovenous fistula (WSS up ~300%) against iliac ligation (WSS down ~60%). Low-flow aneurysms ended up larger; high-flow walls kept more endothelial and smooth muscle cells, made more VEGF-D and PDGF-B, and favoured proliferation over apoptosis 38. Low flow also encouraged adventitial neovascularisation, GM-CSF and macrophages, whereas high flow retained CD34+ progenitors 39—the experimental case for moving the legs to move blood past the aneurysm.

4.3. Endothelial Dysfunction, Mechanotransduction and Interstitial Flow

Laminar flow keeps eNOS running through PI3K/Akt, and NO holds the vessel relaxed and anti-inflammatory; low or oscillating shear instead activates NF-κB and ICAM-1, VCAM-1 and E-selectin, inviting monocytes in 37. A damaged glycocalyx compounds the signalling failure 40, and loss of the junctional VE-cadherin/AmotL2 pathway is itself enough to provoke inflammation and AAA 41; how such intramural forces bear on the thoracic aorta has been reviewed elsewhere 42. Luminal shear is not the only flow at stake: interstitial flow within the wall lowers SM-MHC, smoothelin and calponin and nudges VSMCs toward the synthetic state 43. Inactivity also travels with obesity and disordered sphingolipid metabolism 44; exercise, conversely, improves lipids and lowers high-sensitivity CRP 7, while sedentary metabolism accumulates the oxLDL and cholesterol crystals that switch NLRP3 on 21.

5. Severe Infection: The PAMP–NLRP3–MMP-9 Axis and the Septic Surge

5.1. Epidemiology, Pathogens and Routes of Invasion

An infected (“mycotic”) aneurysm forms when bacteria or fungi breach the wall. It is uncommon—0.7%–2.6% of all aneurysms—but aggressive, with mortality of 30%–50% and thoracic cases that are easy to miss 8,45. Its patients skew younger than degenerative AAA, often under 40 9. Staphylococcus aureus and Salmonella (the nontyphoidal link to aortitis is especially well documented) lead, followed by streptococci and E. coli; fungi appear mainly in the immunosuppressed 8,10,46. Organisms reach the wall by colonising an atheromatous plaque, riding septic emboli into the vasa vasorum, spreading from adjacent infection, entering through trauma or an iatrogenic device, or arriving in endocarditis emboli 10.

5.2. The Inflammatory–Protease Cascade and Sepsis

Once inside, pathogen-associated molecular patterns (PAMPs)—LPS, peptidoglycan, bacterial DNA—are caught by TLR and NOD receptors 8. Neutrophils dump MMP-8, MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL) onto the matrix 8, while macrophages read LPS through TLR4, activate NF-κB and amplify TNF-α, IL-1β and IL-6 11. PAMPs, bacterial DNA, ATP and ROS then engage NLRP3; gasdermin D (GSDMD) pores, circRNA-governed macrophage pyroptosis and VSMC putrescine synthesis have all been implicated in AAA, and here again caspase-1 activates MMP-9 13,47,48. Proteases, ROS and toxins necrose the wall, collapse its elastin and collagen and end in pseudoaneurysm or rupture 9. Even without invasion, sepsis floods the circulation with cytokines that drive MMPs and apoptosis in wall cells 11, and hypotension and vasopressors worsen perfusion; that this raises rupture risk is mechanistically plausible but still awaits a proper cohort.

5.3. IL-1β as the Connecting Cytokine

IL-1β is where infection and aneurysm most clearly meet. Knocking IL-1β out, or blocking its receptor with anakinra, curbed experimental TAA and AAA 49; and CANTOS showed that canakinumab, an anti-IL-1β antibody, lowers systemic inflammation and atherothrombotic events—indirect support, but real, for the same move in aneurysm 21.

6. A Convergent, Synergistic Network with NLRP3 at Its Core

The upstream stories differ; the downstream wiring does not, and Table 1 and Figure 1 lay this out. Cold arrives by eCIRP–TLR4 and sympathetic stress, inactivity by low, oscillating shear and a dysfunctional endothelium, infection by PAMP–TLR/NOD. Each feeds NF-κB, NLRP3, MMP-2/9, oxidant stress and VSMC dysfunction, and NLRP3-derived caspase-1 is the choke point at which mature cytokines and direct MMP-9 activation meet.
Winter makes the synergy concrete. Cold leaves CIRP and sympathetic pathways switched on, and a respiratory infection on top drives PAMP–NLRP3 signalling hard, spiking IL-1β and MMP-9 enough to tip a vulnerable wall into dissection or rupture—consistent with the winter peak in events 4. Inactivity works the other side of the same coin: with less NO and more oxLDL, the wall simply has less reserve against cold or infection. Combined, the effect is networked rather than additive.

7. From Single-Omics to Integrated Multi-Omics

7.1. What Single-Omics Has Revealed—And Where It Falls Short

Each omics layer has been turned on aneurysm, one at a time. scRNA-seq found Malat1+ VSMCs and other disease subsets 50; spatial transcriptomics placed GPNMB+ macrophages where the elastic lamina was most damaged, driving VSMC switching through CD44 51, and mapped distinct changes around CRP deposits 52. Proteomics named CXCR4 a shared marker of inflammatory cells and vessels for imaging 53, and ECM proteomics logged changes in collagen XII, thrombospondin-2 and periostin while catching MMP-12 as a substrate for several matrix glycoproteins 54. Taurine reprogramming and lactylation joined the metabolic side 55,56, and the microRNA layer has been reviewed on its own 57. Useful as these are, one layer shows only one dimension, and a transcript is a poor proxy for a protein’s amount or timing; single-omics can neither reconstruct the cell–microenvironment web nor tell a driver from a bystander 58.

7.2. Integrated Multi-Omics in Other Vascular Diseases

scRNA-seq has already catalogued VSMC and endothelial subsets across AAA and dissection 18,59,60. Atherosclerosis shows what adding layers can buy. Joint CITE-seq (transcriptome plus surface protein) and scRNA-seq resolved dozens of multimodal states, TREM2+ and SMC-derived foam cells among them, and set symptomatic against asymptomatic plaque 61; fate mapping combined with scRNA-seq and human genetics traced the SMC-to-“SEM” intermediate and flagged retinoic-acid signalling as a lever 62. The comparative point is simple: cross-layer analysis exposes what any single layer misses.

7.3. Current State and Gaps in Aneurysm

Aneurysm still lags. Most studies hold to one transcriptome or one metabolome and never cross genome, transcript, protein and metabolite. Pairing scRNA-seq with micro-mechanical devices implicated Piezo1 in VSMC mechanosensing 63; pairing it with scATAC-seq showed DNA damage pushing VSMCs from contractile to inflammatory through STING–IRF3 64; and complement and precision-medicine ideas are only now arriving 65. scRNA-seq also throws away position and often needs pooled donors, gaps spatial methods partly fill 66. Some open questions are still basic: do TAA and AAA, or aneurysms driven by infection, cold, trauma or sedentary flow, even carry distinguishable signatures? Most human-relevant comparisons rest on a single acute animal model.

7.4. Application Prospects

Risk stratification is the first payoff within reach: layered signatures might tell an indolent aneurysm from a fast-growing one when the two look identical on imaging. Running the same omics in parallel across stressors could map wall-degeneration modules and settle whether the risk factors share a module or use separate routes. Combined plasma proteomics, metabolomics and lipidomics could supply non-invasive markers, alongside MMP-9, desmosine and 18F-FDG PET, which already predict growth of small AAA 67–70; tying GWAS hits to particular cell-type transcriptomes gives a target genetic backing 71. Around 23 AAA loci are known 72,73; lipid genetics and Mendelian randomisation argue for causal LDL-C and triglyceride effects and implicate HMGCR, CETP, PCSK9 and the IL-6R, PLAU and PSMA4 loci 74,75, while proteomic genetics added neogenin and KIT ligand 76. Enthusiasm should be tempered: CITE-seq, scATAC-seq and spatial methods are expensive and underpowered, and stable signatures await large, multicentre, paired tissue–blood cohorts.

8. Therapeutic Targets and Translational Challenges

A handful of candidates have reached animals or the clinic (Table 2). Doxycycline, roxithromycin and the statins have not produced a drug that stops expansion 77,78. NLRP3, sitting at the convergence point, draws the most interest: the selective inhibitor MCC950 limited dilatation, dissection and rupture in hyperlipidaemic, Ang II-infused mice, partly by blocking caspase-1-driven MMP-9 activation 13; colchicine blocks NLRP3 assembly through microtubules and has cardiovascular outcome-trial support (COLCOT, LoDoCo2), though no direct AAA test exists; and the approved sulphonylurea glyburide inhibits NLRP3 and lessened Ang II-induced AAA/dissection 20. Downstream, canakinumab and anakinra target IL-1β 21,49, anti-CIRP antibody limited rat AAA 29, and the eCIRP-derived M3 peptide, which interrupts eCIRP–TREM-1, lifted survival from 40% to 80% in intestinal ischaemia–reperfusion 26.

8.1. NLRP3 Inhibitors

None of this is straightforward. MCC950 stalled after hepatic safety signals. Colchicine has a narrow window, with gastrointestinal and muscle toxicity in older patients and several cardiovascular interactions. Glyburide would need doses above its hypoglycaemic range to hit NLRP3, bringing hypoglycaemia straight back. Because NLRP3 also defends against infection, chronic blockade carries an infectious cost, and a dedicated AAA randomised trial does not yet exist.

8.2. CIRP-Directed Therapy

Anti-CIRP antibody protects rats 29 and M3 disrupts eCIRP–TREM-1 26, but neither has reached patients, and CIRP’s everyday role in coping with stress argues against blocking it for long. Serum CIRP may prove more useful sooner as a marker of cold-related risk than as a drug target.

8.3. Exercise, Stratified by Aneurysm Status

Regular leg exercise raises flow and WSS, helps the endothelium, lowers systemic inflammation and improved inflammatory markers in small-AAA training studies 79. Above 5.5 cm, or during rapid expansion, hard exercise and Valsalva manoeuvres are best avoided; today’s guidance leans on expert consensus 80, and diameter-specific safety data simply do not exist.

8.4. IL-1β Blockade

The best IL-1β evidence still comes from coronary disease rather than AAA: canakinumab cut recurrent events after myocardial infarction in CANTOS 21, and anakinra checked experimental TAA/AAA 49. CANTOS also saw more fatal infections on treatment, a genuine worry in older patients; canakinumab is costly and anakinra must be injected daily. Whether either helps in AAA needs its own trial.

9. Limitations and Future Directions

Much of the synergy here is inferred from mechanism and pairwise evidence; no model yet puts single and combined exposures head to head. Cold evidence is epidemiological or based on acute exposure, inactivity evidence leans on questionnaires, and AAA drug evidence lacks large trials—and, as a narrative review, we cannot exclude selection bias. Technically, integrated single-cell and spatial omics, aortic organoids and organ-on-chip devices could compare stressors and screen drugs with fewer animals; models that combine cold, infection and disturbed flow are needed to measure synergy, thresholds and any window of susceptibility. The most realistic near-term moves are serum CIRP as a predictor and phase-II trials of colchicine or glyburide in 3.0–4.5 cm AAA with expansion rate as the primary endpoint, alongside graded exercise prescriptions and risk models that fold temperature, activity and infection history in with the standard factors.

10. Conclusions

Cold, inactivity and infection start in different places and finish in much the same one: NF-κB, NLRP3, MMP-2/9, oxidant stress and a wall stripped of contractile VSMCs. NLRP3-derived caspase-1 is the unusual step, releasing IL-1β/IL-18 and activating MMP-9 at the same moment. Winter’s “double hit” and the sedentary wall’s loss of reserve are simply that network in everyday life.
The drugs remain preclinical or borrowed from other diseases, and their problems—hepatic toxicity, narrow windows, infection risk—are unresolved; exercise, keeping warm in winter and respiratory vaccination are available now. The next stage, in our view, is less about adding single-exposure observations and more about multifactorial models, multicentre multi-omics cohorts and early trials judged by how fast the aneurysm grows.

Author Contributions

Cheng Hu: conceptualization, literature retrieval and screening, data curation, formal analysis, writing–original draft, writing–review & editing, and supervision.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. [Replace if a grant number is to be declared.].

Acknowledgments

The author thanks the Wu Lien-teh Honors Program of Harbin Medical University for academic training.
Declaration of generative AI and AI-assisted technologies in the writing process: During the preparation of this work the authors used [name of AI tool/service] in order to improve English language and readability. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

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Preprints 233631 g001
Figure 1. How three modifiable factors converge to accelerate aortic aneurysm. Cold engages eCIRP–TLR4/TREM-1 and sympathetic stress; inactivity generates low, oscillatory wall shear stress and endothelial dysfunction; infection presents PAMPs to TLR/NOD receptors. Different as these are upstream, all reach the NLRP3 inflammasome/caspase-1, which releases IL-1β/IL-18, drives pyroptosis and cleaves pro-MMP-9. Inflammation, MMP-2/9 activity, VSMC loss and oxidant stress then reinforce one another and progressively destroy the wall, ending in expansion, dissection and rupture. Drawn by the authors from references 7,8,13,20,21,27.
Figure 1. How three modifiable factors converge to accelerate aortic aneurysm. Cold engages eCIRP–TLR4/TREM-1 and sympathetic stress; inactivity generates low, oscillatory wall shear stress and endothelial dysfunction; infection presents PAMPs to TLR/NOD receptors. Different as these are upstream, all reach the NLRP3 inflammasome/caspase-1, which releases IL-1β/IL-18, drives pyroptosis and cleaves pro-MMP-9. Inflammation, MMP-2/9 activity, VSMC loss and oxidant stress then reinforce one another and progressively destroy the wall, ending in expansion, dissection and rupture. Drawn by the authors from references 7,8,13,20,21,27.
Preprints 233631 g001
Table 1. How the three modifiable factors activate shared pathogenic pathways in the aortic wall.
Table 1. How the three modifiable factors activate shared pathogenic pathways in the aortic wall.
Shared pathway Chronic cold Physical inactivity Severe infection
NF-κB inflammation eCIRP→TLR4→MyD88→NF-κB 24,27 Low/oscillatory WSS→endothelial NF-κB 37 PAMPs→TLR/NOD→NF-κB 8,11
NLRP3 inflammasome ROS + DAMP (eCIRP), indirect 32 oxLDL/cholesterol crystals + mechanical stress 21 PAMPs + bacterial DNA + ATP, direct 13
MMP-2/9 up-regulation CIRP induces endothelial MMP-2, macrophage MMP-9 27,29 Low WSS→VSMC switch→MMP secretion 16,38 Leukocyte degranulation + caspase-1 activation 8,13
Oxidative stress NADPH oxidase + antioxidant deficit 32 eNOS uncoupling + ROS 37 Neutrophil burst + mitochondrial ROS 8
VSMC dysfunction Sympathetic/Ang II→switch, apoptosis 2,30 Altered interstitial flow→loss of contractile proteins 43 IL-1β/TNF-α→caspase-1 degrades contractile proteins 20
Table 2. Candidate interventions for aortic aneurysm and their stage of development.
Table 2. Candidate interventions for aortic aneurysm and their stage of development.
Strategy Representative agent Mechanism Stage
NLRP3 inhibitor MCC950 (CRID3) Blocks inflammasome assembly, caspase-1 and MMP-9 cleavage 13 Preclinical (mouse AAA)
NLRP3 inhibitor Colchicine Microtubule inhibition of NLRP3; lowers IL-1β/MMP-9 CV outcome trials (COLCOT, LoDoCo2); AAA RCT lacking
NLRP3 inhibitor Glyburide Approved sulphonylurea that inhibits NLRP3; reduces Ang II-induced AAA/dissection 20 Preclinical; repurposing candidate
IL-1β target Canakinumab Anti-IL-1β antibody; lowers vascular inflammation/events in CANTOS 21 Phase III (CV); AAA untested
IL-1β target Anakinra IL-1 receptor antagonist; limits experimental TAA/AAA 49 Preclinical; approved (RA)
CIRP target Anti-CIRP antibody Blocks eCIRP–TLR4/TREM-1; limits AAA and MMP-2/9 29 Preclinical (rat AAA)
CIRP target M3 peptide Disrupts eCIRP–TREM-1; reduces systemic inflammation 26 Preclinical (ischaemia–reperfusion)
Non-pharmacological Aerobic exercise Raises WSS, improves endothelial function, lowers hs-CRP and lipids 7,38,79 Epidemiological evidence; RCT needed
Non-pharmacological Thermoprotection + vaccination Reduces cold exposure; influenza/pneumococcal vaccination limits inflammatory surges 4 Recommended; low cost
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