Highlights
- High circulating VCAM-1 levels are independently associated with adverse cardiovascular outcomes in patients with HFrEF.
- ICAM-1 systemic concentrations do not predict heart failure progression or mortality, indicating distinct roles for adhesion molecules.
- Dapagliflozin reduces heart failure events consistently across all VCAM-1 levels, underscoring its broad clinical efficacy independent of inflammatory biomarker status.
- VCAM-1 may reflect underlying inflammatory and immune-mediated pathophysiology in chronic heart failure, offering potential new angles for biomarker-guided therapy.
Background
Chronic heart failure, particularly heart failure with reduced ejection fraction (HFrEF), remains a major cause of morbidity and mortality worldwide despite advances in therapy. Inflammation and immune system activation have been increasingly recognized as critical contributors to heart failure pathogenesis and progression. Cellular adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1), mediate leukocyte adhesion and transmigration, central processes in vascular inflammation.
Systemic VCAM-1 levels have been previously linked to incident heart failure and cardiovascular events in epidemiological cohorts, yet their prognostic value in established HFrEF had been less well defined. Understanding whether VCAM-1 and ICAM-1 independently associate with heart failure progression could illuminate mechanistic pathways and refine risk stratification.
Key Content
Chronological and Contextual Development of Evidence
Early observational studies established that elevated circulating adhesion molecules correlate with endothelial dysfunction and adverse cardiovascular outcomes. VCAM-1, expressed on activated endothelium, facilitates immune cell recruitment and contributes to myocardial inflammation and remodeling. Subsequent cohorts linked higher VCAM-1 plasma levels with incident heart failure, but data stratified by heart failure subtype and rigorous outcome adjudication were lacking.
The DAPA-HF trial (2019) demonstrated that dapagliflozin improved outcomes in patients with HFrEF; the biomarker substudy published by McDowell et al. (2025) provides pivotal randomized clinical trial evidence correlating baseline VCAM-1 levels with heart failure progression and mortality.
VCAM-1 and ICAM-1 as Prognostic Biomarkers in HFrEF
McDowell et al. analyzed 3051 patients from the DAPA-HF biomarker substudy, capturing a global, diverse cohort with symptomatic HFrEF (NYHA II-IV). Baseline median VCAM-1 was 997 ng/mL, with higher tertiles linked to older age, worse functional status, elevated NT-proBNP and hs-TnT levels, and impaired renal function, reflecting more advanced disease.
After adjustment for established prognostic markers (eGFR, NT-proBNP, hs-TnT, hs-CRP), patients in the highest VCAM-1 tertile exhibited a 40% higher risk of the composite outcome of worsening HF or cardiovascular death (adjusted HR 1.40, 95% CI 1.11-1.77; P = .004) compared to the lowest tertile. The risk increment was consistent across other outcomes, including all-cause mortality. Conversely, ICAM-1 levels showed no significant association with outcomes.
These findings underscore a specific role for VCAM-1, potentially reflecting distinct inflammatory or immune pathways in HFrEF pathophysiology, beyond classic neurohumoral and myocardial injury markers.
Effect of Dapagliflozin in Relation to Adhesion Molecule Levels
Importantly, dapagliflozin’s efficacy in reducing the primary outcome was consistent across all VCAM-1 tertiles (HR ranging from 0.76 to 0.82; P for interaction = .93). This indicates that the benefit of SGLT2 inhibition is robust regardless of baseline inflammatory biomarker status.
No significant changes in VCAM-1 levels were observed after 12 months of treatment, suggesting that dapagliflozin’s cardioprotective effects may not directly modulate systemic adhesion molecule concentrations but rather act via complementary mechanisms.
Other Relevant Studies and Meta-Analyses
Prior meta-analyses of inflammatory biomarkers in heart failure have consistently reported that multiple inflammatory mediators correlate with adverse outcomes, but adhesion molecules have been less studied in randomized trial populations. The DAPA-HF biomarker substudy fills this gap, combining rigorous outcome adjudication and adjustment for competing biomarkers.
Mechanistic studies in preclinical models correlate endothelial VCAM-1 expression with myocardial fibrosis and immune cell infiltration, reinforcing the translational relevance of these clinical biomarker findings.
Expert Commentary
This comprehensive analysis from the DAPA-HF biomarker substudy adds robust evidence linking VCAM-1 levels with heart failure progression and mortality risk. It highlights a potentially underappreciated inflammatory/immune axis in HFrEF, distinct from traditional neurohumoral activation markers.
Clinically, VCAM-1 could serve as an adjunct prognostic biomarker to refine risk stratification, especially in patients with advanced heart failure or those not optimally phenotyped by natriuretic peptides alone. Its lack of association with ICAM-1 underscores the specificity among adhesion molecules, inviting further mechanistic exploration.
The consistent benefit of dapagliflozin regardless of VCAM-1 level supports its broad application but indicates that modulation of vascular adhesion-related inflammation is not the primary mechanism of benefit. This insight prompts further research into complementary pathways, including direct myocardial, renal, and metabolic effects of SGLT2 inhibitors.
Limitations include a single measurement time point for adhesion molecules at baseline and 12 months, limiting trajectories over longer follow-up. The observational nature of biomarker-outcome association precludes causal inferences. Additionally, the study population was predominantly male and of a specific heart failure phenotype (HFrEF), warranting cautious extrapolation to other HF subtypes.
Conclusion
The DAPA-HF biomarker substudy elucidates a significant association between elevated circulating VCAM-1 and adverse outcomes in chronic HFrEF, independent of conventional prognostic markers. VCAM-1 emerges as a meaningful biomarker of the inflammatory-immune dimension of heart failure pathophysiology and progression.
Dapagliflozin’s consistent benefit across VCAM-1 strata affirms its role in standard HFrEF treatment and suggests that inflammatory adhesion pathways represent a parallel but distinct therapeutic target. Future research should investigate whether targeting VCAM-1 mediated pathways can improve heart failure outcomes and the potential integration of adhesion molecule profiling into personalized care algorithms.
References
- McDowell K, Welsh P, Docherty KF, et al. Cellular Adhesion Molecules and Adverse Outcomes in Chronic Heart Failure: Findings From the DAPA-HF Randomized Clinical Trial. JAMA Cardiol. 2025;10(8):797-808. doi:10.1001/jamacardio.2025.1592
- McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008. doi:10.1056/NEJMoa1911303
- Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61(10):2108-2117. doi:10.1007/s00125-018-4714-2
- Mann DL. Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ Res. 2015;116(7):1254-1268. doi:10.1161/CIRCRESAHA.116.303584
- Zhang M, An Z, Gao Y, et al. Role of endothelial adhesion molecules in heart failure: a systematic review. Int J Cardiol. 2023;367:173-180. doi:10.1016/j.ijcard.2023.04.047
