Cooling the fire: targeting inflammation in cardiovascular diseases

Inflammation has emerged as a central driver of atherosclerosis and its complications, reshaping our understanding of cardiovascular disease beyond traditional lipid-centric paradigms. From early vascular aging to residual risk after optimal medical treatment, multiple lines of evidence suggest that inflammatory pathways are a major target for reducing cardiovascular risk. In this issue, we present a series of full research papers that explore the ‘fire’ within our arteries—from novel biomarkers and mechanistic pathways to therapeutic interventions. To cool the fire, we must first identify who is burning. In Factors associated with elevated high-sensitivity C-reactive protein levels in individuals with atherosclerotic cardiovascular disease in the USA and the UK, Ray et al.1 (UK) analyze data from the UK Biobank and NHANES to identify potential factors associated with elevated high-sensitivity C-reactive protein (hsCRP). Obesity, overweight, smoking, female sex, and higher LDL-cholesterol and triglyceride levels were all associated with elevated hsCRP, whereas statin use was associated with lower odds of elevated hsCRP. Even among statin-treated patients, residual inflammation and triglyceride levels might constitute important prognostic factors. In Prognostic impact of residual inflammatory and triglyceride risk in statin-treated patients with well-controlled LDL cholesterol and atherosclerotic cardiovascular disease, Di Muro et al.2 (USA) studied a large cohort of patients undergoing percutaneous coronary intervention with well-controlled LDL-C. Patients were stratified according to residual inflammatory risk (hsCRP ≥2 mg/L) and residual triglyceride risk. Residual inflammatory risk—whether isolated or combined with hypertriglyceridaemia—was strongly associated with Major Adverse Cardiovascular Events (MACE) and mortality, whereas isolated hypertriglyceridaemia was not (Figure 1). These findings reinforce hsCRP as a key marker for residual risk stratification in statin-treated populations. Cumulative incidence curves of major adverse cardiovascular events stratified by residual inflammatory and triglyceride risk. Patients with residual inflammatory risk (yellow) and combined risk (red) show significantly higher event rates compared with those with no residual risk (green) or isolated triglyceride risk (blue). Reproduced from Di Muro et al.2 The interplay between lipids and inflammation is complex. In The role of systemic inflammation in remnant cholesterol-associated cardiovascular risk: insights from the EPIC-Norfolk study, Kraaijenhof et al.3 (Netherlands) confirmed that remnant cholesterol is strongly associated with systemic inflammation. However, mediation analysis revealed that hsCRP only explains a small fraction (5.9%) of the cardiovascular risk associated with remnant cholesterol, suggesting that remnant cholesterol and inflammation track together but likely require distinct therapeutic targets. Beyond hsCRP, additional inflammatory markers are emerging. In Association of neutrophil-to-lymphocyte ratio with clinical outcomes after percutaneous coronary intervention, Oliva et al.4 (USA) showed that in more than 7000 patients that an elevated neutrophil-to-lymphocyte ratio (NLR) independently predicted MACE, mortality, and bleeding, particularly among patients with acute coronary syndromes or chronic kidney disease (CKD). As a low cost and readily available biomarker, NLR may offer practical value for risk refinement. Moving upstream in the inflammatory cascade, Agboola et al.5 (USA) present The role of inflammation in longitudinal renal function decline and incident chronic kidney disease: the multi-ethnic study of atherosclerosis. Interleukin-6 (IL-6) emerged as a more consistent predictor of renal function decline and incident CKD than hsCRP, suggesting IL-6 as a promising biomarker for renal disease progression. Broadening the perspective to immunity, Jiang et al.6 (China) explored the Association and predictive value of immunoglobulin and complement levels for incident coronary heart disease: a nested case-control study in Chinese adults. Higher levels of IgA and Complement 3 were associated with increased coronary heart disease risk, whereas IgG appeared protective. An ‘immune indicator score’ improved risk prediction beyond traditional risk factors, suggesting a complex interplay between humoral immunity and atherosclerosis. Inflammation also appears to accelerate vascular aging. In High-sensitivity C-reactive protein mediates age-related vascular dysfunction: the Rotterdam Study, Mohammadi Jouabadi et al.7 (Netherlands) showed that systemic inflammation, assessed by hsCRP, mediates the association between aging and both arterial stiffness (pulse wave velocity) and carotid intima–media thickness. The mediation effect was stronger in men and comparable in magnitude to lipids markers. Complementary Mendelian randomization analyses further supported a potential causal link between genetically predicted hsCRP and arterial stiffness. These findings reinforce the concept that systemic inflammation plays a key role in vascular aging, particularly in functional arterial stiffening. The remaining challenge is determining which anti-inflammatory therapies can effectively ‘cool the fire,’ and how they should be used. In this issue, Tucker et al.8 (Australia) examine the role of colchicine in The efficacy and safety of low-dose colchicine in atherosclerotic cardiovascular disease: a systematic review and meta-analysis, providing an updated synthesis of the evidence supporting anti-inflammatory strategies for cardiovascular prevention. Pooling data from 11 trials and over 30 000 participants, they confirm that low-dose colchicine reduces the risk of MACE by 17%, driven by reductions in myocardial infarction (Figure 2). However, no significant benefit was observed for cardiovascular mortality, highlighting the need to identify patient subgroups most likely to benefit. Forest plot of the primary endpoint major adverse cardiovascular events from the meta-analysis of colchicine trials. Colchicine treatment is associated with a significant reduction in the risk of major adverse cardiovascular events compared with control. Reproduced from Tucker et al.8 A potential mechanism for colchicine’s benefit is explored by Baier et al.9 (Denmark) in Colchicine mitigates arterial stiffness in high-risk patients with type 2 diabetes: a randomized placebo-controlled trial. In this study, 6 months of colchicine therapy significantly reduced arterial stiffness assessed by carotid-femoral pulse wave velocity compared with placebo, suggesting that reducing inflammation may improve vascular compliance in these patients. In Ischaemic cardiovascular risk with allopurinol and protective effect of colchicine in gout: a Dutch nationwide pharmaco-epidemiological study, Peeters et al.10 (Netherlands) show that adding colchicine to allopurinol attenuated the transient increase in cardiovascular risk observed after allopurinol initiation alone. Inflammation plays a central role in non-atherosclerotic cardiovascular diseases. In Human intravenous immunoglobulins for recurrent pericarditis: a multicentre cohort study, Collini et al.11 (Italy) reported that intravenous immunoglobulin therapy (IVIG) reduced recurrence rates by 78% in patients with recurrent pericarditis. Emergency department admissions and the need for corticosteroids and anakinra were also significantly reduced, supporting IVIG as a potential last-line anti-inflammatory strategy. Shifting to the myocardium, Li Guangling et al.12 (China) present Predictors of long-term adverse course in acute myocarditis: a multicentre cohort study. They identified a cardiac troponin I threshold above 10 000 pg/mL as a critical predictor of chronic active myocarditis and heart failure, providing a useful biomarker for risk stratification. The papers in this issue illustrate that inflammation is not a monolithic process, but a complex and nuanced risk factor that interacts with lipids, aging and immunity on a wide spectrum of outcomes. While hsCRP remains our standard metric, upstream biomarkers like IL-6 and novel indices like NLR or immune scores offer promising tools for refined risk stratification. Therapeutically, we are entering an era where ‘cooling the fire’ with agents like colchicine is becoming an evidence-based reality for secondary prevention. Victor Aboyans {MD, PhD [Writing—review & editing (supporting)]}, and Alexis F. Guédon [Writing—original draft (lead)]