CDR132L improves systolic and diastolic function in a large animal model of chronic heart failure.
Cardiac remodelling
Chronic heart failure
Contractile function
MicroRNAs
Myocardial infarction
Translational studies
Journal
European heart journal
ISSN: 1522-9645
Titre abrégé: Eur Heart J
Pays: England
ID NLM: 8006263
Informations de publication
Date de publication:
07 01 2021
07 01 2021
Historique:
received:
07
02
2020
revised:
16
07
2020
accepted:
10
09
2020
pubmed:
23
10
2020
medline:
15
5
2021
entrez:
22
10
2020
Statut:
ppublish
Résumé
Cardiac miR-132 activation leads to adverse remodelling and pathological hypertrophy. CDR132L is a synthetic lead-optimized oligonucleotide inhibitor with proven preclinical efficacy and safety in heart failure (HF) early after myocardial infarction (MI), and recently completed clinical evaluation in a Phase 1b study (NCT04045405). The aim of the current study was to assess safety and efficacy of CDR132L in a clinically relevant large animal (pig) model of chronic heart failure following MI. In a chronic model of post-MI HF, slow-growing pigs underwent 90 min left anterior descending artery occlusion followed by reperfusion. Animals were randomized and treatment started 1-month post-MI. Monthly intravenous (IV) treatments of CDR132L over 3 or 5 months (3× or 5×) were applied in a blinded randomized placebo-controlled fashion. Efficacy was evaluated based on serial magnetic resonance imaging, haemodynamic, and biomarker analyses. The treatment regime provided sufficient tissue exposure and CDR132L was well tolerated. Overall, CDR132L treatment significantly improved cardiac function and reversed cardiac remodelling. In addition to the systolic recovery, diastolic function was also ameliorated in this chronic model of HF. Monthly repeated dosing of CDR132L is safe and adequate to provide clinically relevant exposure and therapeutic efficacy in a model of chronic post-MI HF. CDR132L thus should be explored as treatment for the broad area of chronic heart failure.
Identifiants
pubmed: 33089304
pii: 5934677
doi: 10.1093/eurheartj/ehaa791
pmc: PMC7813625
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
192-201Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.
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