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Randomized Controlled Trial
. 2025 Aug 1;10(8):797-808.
doi: 10.1001/jamacardio.2025.1592.

Cellular Adhesion Molecules and Adverse Outcomes in Chronic Heart Failure: Findings From the DAPA-HF Randomized Clinical Trial

Kirsty McDowell  1 , Paul Welsh  1 , Kieran F Docherty  1 , David A Morrow  2 , Pardeep S Jhund  1 , Rudolf A De Boer  3 , Eileen O'Meara  4 , Silvio E Inzucchi  5 , Lars Køber  6 , Mikhail N Kosiborod  7 , Felipe A Martinez  8 , Piotr Ponikowski  9 , Ann Hammarstedt  10 , Anna Maria Langkilde  10 , Scott D Solomon  11 , Naveed Sattar  1 , Marc S Sabatine  2   12 , John J V McMurray  1
Affiliations
Randomized Controlled Trial

Cellular Adhesion Molecules and Adverse Outcomes in Chronic Heart Failure: Findings From the DAPA-HF Randomized Clinical Trial

Kirsty McDowell et al. JAMA Cardiol. .

Abstract

Importance: Vascular cell adhesion molecule 1 (VCAM-1) and intracellular cell adhesion molecule 1 (ICAM-1) are responsible for immune cell-cell interactions. Systemic levels of VCAM-1 are associated with incident heart failure (HF).

Objectives: To determine if VCAM-1 and ICAM-1 levels are associated with progression of established HF.

Design, setting, and participants: Participants enrolled in the biomarker substudy of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) randomized clinical trial had VCAM-1 and ICAM-1 levels measured at baseline and 12 months. The DAPA-HF trial was conducted at 410 sites in 20 countries. Patients with HF and reduced ejection fraction (HFrEF) in New York Heart Association (NYHA) class II to IV with elevated natriuretic peptides were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Data were analyzed from January 2023 to January 2025.

Interventions: Dapagliflozin, 10 mg, once daily vs placebo.

Main outcomes and measures: The primary outcome was the composite of a worsening HF event or cardiovascular death. The associations between VCAM-1 and ICAM-1 levels at baseline and the primary outcome, its components, and all-cause death were analyzed using Cox proportional hazards regression models adjusted for known prognostic variables including estimated glomerular filtration rate (eGFR), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hs-TnT), as well as high-sensitivity C-reactive protein.

Results: A total of 3051 participants (mean [SD] age, 67.2 [10.5] years; 2386 male [78.2%]) were included in this study. Mean (SD) follow-up time was 17.6 (5.2) months. The median (IQR) baseline VCAM-1 level was 997 (816.7-1218.8) ng/mL. Compared with patients with lower concentrations of VCAM-1, those with higher concentrations of VCAM-1 were older (mean [SD] age T3 vs T1, 69.7 [9.7] years vs 64.1 [10.7] years; P < .001), in worse NYHA class (T3 vs T1, NYHA class III/IV 35.6% [362 of 1017] vs 26.5% [269 of 1017]; P < .001), and had higher NT-proBNP (median [IQR] T3 vs T1, 2018 [1126-3753] pg/mL vs 1118 [693-1830] pg/mL) and hs-TnT (median [IQR] T3 vs T1, 24.7 [17.1-37.5] ng/L vs 16.6 [11.6-24.9] ng/L) concentrations, and lower eGFR (mean [SD] T3 vs T1, 58.4 [17.6] mL/min/1.73 m2 vs 71.7 [18.0] mL/min/1.73 m2). Patients in tertile 3 of VCAM-1, compared with tertile 1, had the highest risk of each outcome (eg, adjusted hazard ratio [HR] for primary outcome 1.40; 95% CI, 1.11-1.77; P = .004). ICAM-1 level was not associated with an elevated risk of any outcome. The benefit of dapagliflozin vs placebo in reducing the risk of the primary outcome was consistent across VCAM-1 tertiles: HR, 0.76 (95% CI, 0.54-1.06), 0.82 (95% CI, 0.59-1.12), and 0.77 (95% CI, 0.61-0.98) for tertiles 1, 2 and 3, respectively (P for interaction = .93). There was no significant change in VCAM-1 level with dapagliflozin at 52 weeks.

Conclusions and relevance: Results of this substudy of the DAPA-HF randomized clinical trial demonstrate that higher VCAM-1 levels, possibly reflecting a distinct inflammatory/immune pathophysiological pathway in HFrEF, were associated with worse outcomes, even after adjustment for conventional prognostic variables.

Trial registration: ClinicalTrials.gov Identifier: NCT03036124.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Welsh reported receiving grants from AstraZeneca, Roche Diagnostics, Boehringer Ingelheim, Novartis, and personal fees from Novo Nordisk, and Raisio Nutrition outside the submitted work. Dr Docherty reported receiving grants from AstraZeneca, Boehringer Ingelheim, and Roche paid to employer, the University of Glasgow; and speaker, advisory board, and/or travel fees from AstraZeneca, Bayer, FIRE-1, Us2.ai, Boehringer Ingelheim, and Abbott outside the submitted work. Dr Morrow reported receiving grants from AstraZeneca, Abbott, Abiomed Inc, Amgen, Anthos Therapeutics, ARCA Biopharma Inc, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis Pharmaceuticals Inc, Janssen Research and Development LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals Inc, Roche, Saghmos Therapeutics Inc, Siemens Healthcare Diagnostics Inc, Softcell Medical Limited, The Medicines Company, Verve Therapeutics Inc, and Zora Biosciences. Dr Jhund reported receiving grants from Novartis, AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk, Roche, and Analog paid to employer, the University of Glasgow; and serving as director of GCTP Ltd. Dr de Boer reported receiving grants from Alnylam, AstraZeneca, Abbott, Bristol Myers Squibb, Novo Nordisk, and Roche to institution; personal fees from Abbott, AstraZeneca, Bristol Myers Squibb, Novo Nordisk, and Roche; and travel support from Abbott and Novo Nordisk outside the submitted work. Dr O’Meara reported receiving grants from AstraZeneca, with fees paid to institution during the conduct of the study; speaker fees from AstraZeneca, Boehringer Ingelheim, GSK, Novo Nordisk, and Pfizer; and grants from American Regent, Bayer, Cardurion, Novo Nordisk paid to institution outside the submitted work; and consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, and Novartis. Dr Inzucchi reported receiving personal fees from AstraZeneca, Boehringer Ingelheim/Lilly, Novo Nordisk, Merck, Pfizer, and Bayer outside the submitted work. Dr Køber reported receiving speaker fees from Novo Nordisk, Novartis, AstraZeneca, and Boehringer Ingelheim outside the submitted work. Dr Kosiborod reported receiving consultant and/or advisory board fees paid to institution from 35Pharma, Alnylam, Amgen, Applied Therapeutics, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria, Janssen, Lexicon Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Pharmacosmos, Regeneron, Roche, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor, Youngene Therapeutics; grants paid to institution from AstraZeneca, Boehringer Ingelheim, Pfizer; and stock options from Artera Health and Saghmos Therapeutics outside the submitted work. Dr Martinez reported receiving grants from AstraZeneca during the conduct of the study. Dr Ponikowski reported receiving grants or contracts, consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Moderna, MSD, Novartis, Novo Nordisk, Pharmacosmos, Servier, Vifor, and Radcliffe Cardiology outside the submitted work. Dr Hammarstedt reported receiving employee fees and stock options from AstraZeneca outside the submitted work. Dr Langkilde reported being an employee of and receiving stock options from AstraZeneca outside the submitted work. Dr Solomon reported receiving grants from AstraZeneca, Alexion, Alnylam, Applied Therapeutics, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos/BridgeBio, Gossamer, GSK, Ionis, Lilly, National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Tenaya, Theracos, Us2.ai and consulting fees from Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, BMS, Cardior, Cardurion, Corvia, Cytokinetics, GSK, Intellia, Lilly, Novartis, Roche, Theracos, Quantum Genomics, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, Valo outside the submitted work. Dr Sattar reported receiving personal fees from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Menarini-Ricerche, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi and grants from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. Dr Sabatine reported receiving grants from AstraZeneca, Abbott Institutional, Amgen, Anthos, Boehringer Ingelheim, Daiichi Sankyo, IONIS, Marea, Merck, Novartis, Pfizer, Saghmos, Verve Therapeutics to the TIMI Study Group at Brigham and Women’s Hospital; consulting fees from AstraZeneca, Amgen, AMPEL BioSolutions, Anthos Therapeutics, Beren Therapeutics, Boehringer Ingelheim, Dr Reddy’s Laboratories, Fibrogen, Merck, Moderna, Novo Nordisk, Precision BioSciences, Silence Therapeutics; and serving as a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from the following: Abiomed Inc, ARCA Biopharma Inc, Janssen Research and Development LLC, MedImmune, Regeneron Pharmaceuticals Inc, Roche, Siemens Healthcare Diagnostics Inc, Softcell Medical Limited, and Zora Biosciences. Dr McMurray reported receiving payment to the University of Glasgow from AstraZeneca, British Heart Foundation, NIH/NHLBI, Alynylam Pharmaceuticals, Bayer, Cardurion, Cytokinetics, Novartis, Roche; personal (consultant, advisory board, and/or lecture) fees from Alynylam Pharmaceuticals, AnaCardio, AstraZeneca, Bayer, Cardurion, Cytokinetics, Novartis, River BioMedics, Biohaven Pharmaceuticals, Chugai Pharmaceuticals, Protherics Medicine Developments Ltd, DalCor Pharmaceuticals, Alkem Metabolics, Canadian Medical and Surgical Knowledge, Centrix Healthcare, Emcure Pharmaceuticals, Eris Lifesciences, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals, Lupin Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, Translational Medicine Academy, Regeneron, MCI India, Hilton Pharmaceuticals, IMEDIC Pharmaceuticals Micro Labs Ltd, At the Limits Ltd, ARMGO Pharmaceuticals, WCG Clinical Services; and director fees from Global Clinical Trial Partners Ltd outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. A Cubic-Spline Model of the Association Between Baseline Vascular Cell Adhesion Molecule 1 (VCAM-1) and the Risk of Cardiovascular Outcomes
A, Primary composite outcome (worsening heart failure or cardiovascular death). B, Worsening heart failure. C, Cardiovascular death. D, All-cause mortality. The model is adjusted age, sex, race, region, systolic blood pressure, heart rate, ejection fraction, New York Heart Association class, duration of heart failure, previous heart failure hospitalization, diabetes status, atrial fibrillation, ischemic etiology, history of myocardial infarction, history of hypertension, history of stroke, estimated glomerular filtration rate, randomized treatment (dapagliflozin), log high-sensitivity troponin T, log high-sensitivity C-reactive protein, and log N-terminal pro–B-type natriuretic peptide randomized treatment (dapagliflozin), and stratified by diabetes status. The reference is the median value.
Figure 2.
Figure 2.. Incidence of the Primary Composite End Point According to Tertiles of Vascular Cell Adhesion Molecule 1 (VCAM-1) and N-Terminal Pro–B-Type Natriuretic Peptide (NT-proBNP) and High-Sensitivity Troponin T (hs-TnT)
A, Baseline NT-proBNP concentration. B, Baseline hs-TnT concentration.
See this image and copyright information in PMC

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