Dexfenfluramine and Pergolide Cause Heart Valve Disease via Valve Metabolic Reprogramming and Ongoing Matrix Remodeling

Abstract

Several clinical reports indicate that the use of amphetaminic anorectic drugs or ergot derivatives could cause valvular heart disease (VHD). We sought to investigate whether valvular lesions develop in response to long-term oral administration of these drugs and to identify drug-targeted biological processes that may lead to VHD. Treatment of New Zealand White rabbits with pergolide, dexfenfluramine, or high-dose serotonin for 16 weeks induced valvular alterations characterized by extracellular matrix remodeling. Transcriptome profiling of tricuspid valves using RNA sequencing revealed distinct patterns of differentially expressed genes (DEGs) that clustered according to the different treatments. Genes that were affected by the three treatments were functionally enriched for reduced cell metabolism processes. The two drugs yielded more changes in gene expression than serotonin and shared most of the DEGs. These DEGs were mostly enriched for decreased biosynthetic processes, increased cell-matrix interaction, and cell response to growth factors, including TGF-β, which was associated with p38 MAPK activation. Treatment with pergolide specifically affected genes involved in homeostasis, which was corroborated by the activation of the master regulator of cell energy homeostasis, AMPK-α, as well as decreased levels of metabolism-related miR-107. Thus, both pergolide and dexfenfluramine may cause VHD through valve metabolic reprogramming and matrix remodeling.

Microdosing psychedelics and the risk of cardiac fibrosis and valvulopathy: Comparison to known cardiotoxins

“…These diagnoses were independently confirmed by at least two cardiologists, usually using echocardiograms ( Khan et al, 1998 ). A recent rabbit model study also found that dexfenfluramine, the d-enantiomer of fenfluramine, may also cause VHD ( Oury et al, 2020 ). Although fenfluramine and dexfenfluramine were once used as anorexic agents, they have since been withdrawn ( Li and Cheung, 2011 ).…”

“…It has been theorized that 5-HT2BR stimulation activates pro-fibrotic pathways via activation of phospholipase C-β, protein kinase C, Src-P, and transforming growth factor-β1 ( Reid et al, 2013 ). Mitogen-activated protein kinase (MAPK) signaling may also be involved: MAPK signaling pathways can stimulate the activation of cardiac fibroblasts, leading to increased production of extracellular matrix proteins, and activation of ERK and p38 MAPK pathways has been shown to induce fibroblasts ( Oury et al, 2020 ). Notably, however, research comparing various readouts of 5-HT2BR activation in several 5-HT2BR agonists concluded that VHD risk was not associated with one specific marker of 5-HT2BR activation but rather with general potency across a variety of markers, including calcium flux, ERK2 phosphorylation, and arrestin recruitment ( Huang et al, 2009 ).…”

Glucagon-Like Peptide-1 Based Therapies: A New Horizon in Obesity Management

“…Development of antiobesity medication has not been easy, because of unexpected adverse events. Reports of heart valve disease associated with fenfluramine, texfenfluramine, and phentermine raised concerns about drug treatment of obesity since 2000 [10,11]. These products were withdrawn by the U.S. Food and Drug Administration (FDA) in 2011.…”