The American College of Cardiology declared that evidence linking inflammation to atherosclerotic cardiovascular disease "is no longer exploratory but is compelling and clinically actionable" in a scientific statement calling for universal screening of high-sensitivity C-reactive protein in both primary and secondary prevention patients.
The statement emphasizes that residual inflammatory risk—measured through elevated high-sensitivity C-reactive protein (hsCRP)—predicts recurrent events even in optimally treated patients. In a contemporary analysis of 31,245 statin-treated patients from multiple trials, hsCRP proved a stronger predictor of recurrent myocardial infarction, stroke, and cardiovascular death than low-density lipoprotein (LDL) cholesterol levels.
"Because clinicians will not treat what they do not measure, universal screening of hsCRP in both primary and secondary prevention patients, in combination with cholesterol, represents a major clinical opportunity and is therefore recommended," the writing committee stated.
Data showed that after statin therapy, risks of cardiovascular death were greater for patients with higher hsCRP compared with those with higher LDL cholesterol. Patients with hsCRP greater than 2 mg/L and LDL cholesterol less than 70 mg/dL maintained high cardiovascular risk, while those with low hsCRP and elevated LDL cholesterol showed conversely low risk.
Evidence includes the JUPITER trial, which demonstrated a 47% reduction in major cardiovascular events among 17,802 patients with LDL cholesterol less than 130 mg/dL but hsCRP greater than or equal to 2 mg/L treated with rosuvastatin vs placebo over a median 1.9 years. Subsequent analysis showed benefit even in participants without standard modifiable risk factors beyond elevated hsCRP.
In secondary prevention, the CANTOS trial of 10,061 patients with prior myocardial infarction and hsCRP greater than or equal to 2 mg/L demonstrated that canakinumab, a monoclonal antibody targeting interleukin-1β, produced a dose-dependent 15% to 17% reduction in recurrent vascular events independent of any LDL cholesterol change—an effect magnitude comparable to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition.
The US Food and Drug Administration–approved anti-inflammatory agent low-dose colchicine (0.5 mg daily) has demonstrated 25% reductions in recurrent cardiovascular events in the COLCOT and LoDoCo2 trials of patients with chronic stable atherosclerosis. However, colchicine failed to show benefit when initiated during acute STEMI in the CLEAR-SYNERGY trial, raising questions about optimal timing of therapy.
The statement provides specific clinical thresholds: hsCRP levels less than 1, 1 to 3, and greater than 3 mg/L denote lower, average, and higher relative cardiovascular risk respectively. Levels greater than 10 mg/L may reflect acute infection and should be repeated in 2 to 3 weeks, using the lower value for risk prediction.
Inflammation's role extends beyond atherosclerosis. In heart failure, the GISSI-HF trial showed that 1 g daily eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) modestly reduced both all-cause mortality (hazard ratio [HR]: 0.91) and the composite of all-cause mortality and cardiovascular hospitalization (HR: 0.92) in New York Heart Association functional class II to IV patients irrespective of etiology or ejection fraction. Exploratory analysis from CANTOS demonstrated dose-dependent reductions in heart failure hospitalization among patients with prior myocardial infarction and hsCRP greater than 2 mg/L.
For recurrent pericarditis, interleukin-1 blockade has transformed treatment. In the AIRTRIP trial showed interleukin-1 blockade reduced recurrent events from 90% to 18% in patients with idiopathic corticosteroid-dependent pericarditis and greater than or equal to 3 prior recurrences. In RHAPSODY, only 7% of patients continuing rilonacept experienced recurrence compared with 74% of those discontinuing therapy.
The statement identifies specialized pro-resolving lipid mediators derived from omega-3 fatty acids as a promising research area. A 2021 meta-analysis of 40 trials reported that every 1 g/day EPA plus DHA corresponded with 9% and 7% lower risk of myocardial infarction and total coronary heart disease respectively. However, a meta-analysis of 7 trials involving 81,210 patients found long-term marine omega-3 supplementation associated with increased atrial fibrillation risk, particularly at doses greater than 1 g/day (HR: 1.49).
The document notes that not all anti-inflammatory trials have succeeded. The National Institutes of Health–funded CIRT trial found no benefit for low-dose methotrexate in chronic atherosclerosis, with the therapy failing to reduce interleukin-6 or hsCRP levels. Large-scale trials testing the interleukin-6 ligand inhibitor ziltivekimab in chronic kidney disease, heart failure with preserved ejection fraction and acute coronary ischemia are underway, with results anticipated in late 2026 or early 2027.
Clonal hematopoiesis of indeterminate potential—characterized by somatic mutations in hematopoietic stem cells—has emerged as an inflammation-linked risk factor associated with 2-fold increased cardiovascular disease risk in general populations and greater than 3-fold increased death risk in ischemic heart failure. In CANTOS, canakinumab produced a 62% relative risk reduction in major adverse cardiovascular events among patients carrying Ten-Eleven Translocation-2 mutations compared with those without clonal hematopoiesis.
Regarding lifestyle, the PREDIMED trial showed that a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced major cardiovascular events compared with low-fat diet (HR for olive oil: 0.69; HR for nuts: 0.72). Chronic physical activity reduces resting C-reactive protein through decreased cytokine production by adipose tissue, skeletal muscles, and endothelial cells, while also increasing specialized pro-resolving mediator production.
The statement cautioned that colchicine should be limited to patients with preserved renal and hepatic function and temporarily stopped if used with interacting therapies such as clarithromycin, ketoconazole, fluconazole, or cyclosporin. Despite evidence of efficacy and safety, utilization of low-dose colchicine in the US and globally remains low.
"The time is also ripe for the development of strategies to promote increased physician awareness of the crucial role of inflammation in CVD [cardiovascular disease] and accelerate the adoption of evidence-based, guideline-directed anti-inflammatory therapy through dissemination and implementation research," the committee concluded. "The time for action has arrived."
Source: JACC