Lactate Dehydrogenase B and Pyruvate Oxidation Pathway Associated With Carfilzomib-Related Cardiotoxicity in Multiple Myeloma Patients: Result of a Multi-Omics Integrative Analysis

• DOI: 10.3389/fcvm.2021.645122
• Publication Date: 2021-04-29T04:30:10Z
• Authors: Marwa Tantawy; Lakshmi Manasa Ch...; Yimei Huang; Timothy J. Garrett; Sonal Singh; Chintan P. Shah; Robert F. Cornell; Rachid C. Baz; Michael G. Fradley; Nida Waheed; David L. DeRemer; Lihui Yuan; Taimour Langaee; Keith March; Carl J. Pepine; Jan S. Moreb; Yan Gong
• Keywords: Cardiotoxicity

Multiple myeloma (MM) is the second most frequent hematologic cancer in United States. Carfilzomib (CFZ), an irreversible proteasome inhibitor being used to treat relapsed and refractory MM, has been associated with cardiotoxicity, including heart failure. We hypothesized that a multi-omics approach integrating data from different omics would provide insights into mechanisms of CFZ-related cardiovascular adverse events (CVAEs). Plasma samples were collected 13 MM patients treated CFZ (including 7 CVAEs 6 no CVAEs) at University Florida Health Cancer Center. These evaluated global metabolomic profiling, proteomic microRNA (miRNA) profiling. Integrative pathway analysis was performed identify genes pathways differentially expressed between without CVAEs. The proteomics identified up-regulation lactate dehydrogenase B (LDHB) [fold change (FC) = 8.2, p 0.01] who experienced metabolomics lower plasma abundance pyruvate (FC 0.16, 0.0004) higher 2.4, 0.0001) Differential expression miRNAs profiling mir-146b be up-regulatein 14, 0.046) CVAE. Pathway suggested fermentation CFZ-CVAEs. In this pilot integrative analysis, we observed down-regulation LDHB among CVAEs, suggesting importance oxidation mitochondrial dysfunction. Validation further investigation larger independent cohort are warranted better understand