Reaffirmation of Mechanistic Proteomic Signatures Accompanying SGLT2 Inhibition in Patients With Heart Failure - Pôle scientifique Biologie, Médecine, Santé
Article Dans Une Revue Journal of the American College of Cardiology Année : 2024

Reaffirmation of Mechanistic Proteomic Signatures Accompanying SGLT2 Inhibition in Patients With Heart Failure

1 Imperial College London
2 Baylor Heart and Vascular Institute
3 Cardiovascular Research and Development Center (UnIC@RISE)
4 Universidade do Porto = University of Porto
5 Baylor Scott and White Research Institute [Dallas, TX, USA]
6 UMMC - University of Mississippi Medical Center
7 NKUA - National and Kapodistrian University of Athens
8 “Attikon” University Hospital
9 Massachusetts General Hospital [Boston]
10 Baim Institute for Clinical Research Boston MA
11 Boehringer Ingelheim Pharma GmbH & Co. KG
12 JGU - Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University
13 LSHTM - London School of Hygiene and Tropical Medicine
14 University Medical Center of the Johannes Gutenberg-University Mainz
15 Boehringer Ingelheim International GmbH
16 Elderbrook Solutions GmbH
17 University of Glasgow
18 DZHK - German Center for Cardiovascular Research
19 Berlin Institute of Health Center for Regenerative Therapies (BCRT)
20 BCRT - Berlin-Brandenburg Center for Regenerative Medicine [Berlin, Germany]
21 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
22 DCAC - Défaillance Cardiovasculaire Aiguë et Chronique
23 CIC-P - Centre d'investigation clinique plurithématique Pierre Drouin [Nancy]
24 INI-CRCT - Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy]
25 Cardiovascular & Renal Clinical Trialists - CRCT - French-Clinical Research Infrastructure Network - F-CRIN [Paris]
26 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
Naveed Sattar

Résumé

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-

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Dates et versions

hal-04694584 , version 1 (11-09-2024)

Identifiants

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Milton Packer, João Pedro Ferreira, Javed Butler, Gerasimos Filippatos, James L Januzzi, et al.. Reaffirmation of Mechanistic Proteomic Signatures Accompanying SGLT2 Inhibition in Patients With Heart Failure. Journal of the American College of Cardiology, 2024, Online ahead of print. ⟨10.1016/j.jacc.2024.07.013⟩. ⟨hal-04694584⟩
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