Portal de investigação
Reaffirmation of Mechanistic Proteomic Signatures Accompanying SGLT2 Inhibition in Patients With Heart Failure: A Validation Cohort of the EMPEROR Program
Data de publicação:
Autores da FMUP
Participantes de fora da FMUP
- Packer M.
- Butler J.
- Filippatos G.
- Januzzi J.L.
- Jr.
- González Maldonado S.
- Panova-Noeva M.
- Pocock S.J.
- Prochaska J.H.
- Saadati M.
- Sattar N.
- Sumin M.
- Anker S.D.
- Zannad F.
Unidades de investigação
Abstract
Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a distinctive pattern of direct biological effects on the heart and kidney under experimental conditions, but the meaningfulness of these signatures for patients with heart failure has not been fully defined. Objectives: We performed the first mechanistic validation study of large-scale proteomics in a double-blind randomized trial of any treatment in patients with heart failure. Methods: In a discovery cohort from the EMPEROR (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and Reduced Ejection Fraction) program, we studied the effect of randomized treatment with placebo or empagliflozin on 1,283 circulating proteins in 1,134 patients with heart failure with a reduced or preserved ejection fraction. In a validation cohort, we expanded the number to 2,155 assessed proteins, which were measured in 1,120 EMPEROR participants who had not been studied previously. Results: In the validation cohort, 25 proteins were the most differentially enriched by empagliflozin (ie, =15% between-group difference and false discovery rate <1% at 12 weeks with known effects on the heart or kidney): 1) 13 proteins promote autophagy and other cellular quality-control functions (IGFBP1, OTUB1, DNAJB1, DNAJC9, RBP2, IST1, HSPA8, H-FABP, FABP6, ATPIFI, TfR1, EPO, IGBP1); 2) 12 proteins enhance mitochondrial health and ATP production (UMtCK, TBCA, L-FABP, H-FABP, FABP5, FABP6, RBP2, IST1, HSPA8, ATPIFI, TfR1, EPO); 3) 7 proteins augment cellular iron mobilization or erythropoiesis (TfR1, EPO, IGBP1, ERMAP, UROD, ATPIF1, SNCA); 4) 3 proteins influence renal tubular sodium handling; and 5) 9 proteins have restorative effects in the heart or kidneys, with many proteins exerting effects in >1 domain. These biological signatures replicated those observed in our discovery cohort. When the threshold for a meaningful between-group difference was lowered to =10%, there were 58 additional differentially enriched proteins with actions on the heart and kidney, but the biological signatures remained the same. Conclusions: The replication of mechanistic signatures across discovery and validation cohorts closely aligns with the experimental effects of SGLT2 inhibitors. Thus, the actions of SGLT2 inhibitors—to promote autophagy, restore mitochondrial health and production of ATP, promote iron mobilization and erythropoiesis, influence renal tubular ion reabsorption, and normalize cardiac and renal structure and function—are likely to be relevant to patients with heart failure. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction [EMPEROR-Preserved], NCT03057951; EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced], NCT03057977) © 2024 The Authors
Dados da publicação
- ISSN/ISSNe:
- 1558-3597, 0735-1097
- Tipo:
- Article
- Páginas:
- 1979-1994
- Link para outro recurso:
- www.scopus.com
Journal of the American College of Cardiology Elsevier USA
Citações Recebidas na Scopus: 3
Documentos
- Não há documentos
Filiações
Keywords
- Aged; Benzhydryl Compounds; Cohort Studies; Double-Blind Method; Female; Glucosides; Heart Failure; Humans; Male; Middle Aged; Proteomics; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume; adenosine triphosphate; autophagy; C X C motif chemokine 6; calcitonin; carcinoembryonic antigen; CD71 antigen; creatine kinase; CSK homologous kinase; empagliflozin; erythropoietin; fatty acid binding protein; fatty acid binding protein 2; fatty acid binding protein 5; fatty acid binding protein 6; gastrotropin; ghrelin; glucose; heat shock cognate protein 70; heat shock protein 40; iron; oncostatin M; osteopontin; programmed cell death protein 5; promotilin; protein glutamine g glutamyltransferase 2; protein p53; proton transporting adenosine triphosphate synthase; retinol binding protein 2; sodium glucose cotransporter 2 inhibitor; somatomedin binding protein 1; tiprelestat; trefoil factor 1; tubulin folding cofactor A; tumor necrosis factor; Twist related protein 1; ubiquitin aldehyde bindi
Proyectos asociados
Dapagliflozin, Spironolactone or Both for HFpEF (SOGALDI-PEF) - NCT05676684
Investigador Principal: João Pedro Melo Marques Pinho Ferreira
Ensaio Clínico Académico (SOGALDI-PEF) . AstraZeneca . 2022
Initiation of ARNi and SGLT2i in Patients With HFrEF: Randomized Open-label Trial (INITIATE-HFrEF) -NCT05989503
Investigador Principal: João Pedro Melo Marques Pinho Ferreira
Ensaio Clínico Académico (INITIATE-HFrEF) . Novartis . 2023
Citar a publicação
Packer M,Ferreira JP,Butler J,Filippatos G,Januzzi JL,JR,González S,Panova M,Pocock SJ,Prochaska JH,Saadati M,Sattar N,Sumin M,Anker SD,Zannad F. Reaffirmation of Mechanistic Proteomic Signatures Accompanying SGLT2 Inhibition in Patients With Heart Failure: A Validation Cohort of the EMPEROR Program. J. Am. Coll. Cardiol. 2024. 84. (20):p. 1979-1994. IF:24,000. (1).
