Inter-Individual Variation and Cardioprotection in Anthracycline-Induced Heart Failure

Abstract

Anthracyclines are one of the most widely used and effective chemotherapies in oncology, but their most important side effect is the cumulative, dose-related cardiotoxicity leading to congestive heart failure in ~5% of individuals. Methodology and pharmacogenetic studies for predicting which individuals are at high risk and subsequently the development of targeted and individualized cardioprotective plans are beginning to make progress. Here, we review current putative risk genes and variants, the strength of evidence for each genetic association and the interaction between risk genes, in the context of known clinical risk factors and potential novel cardioprotective strategies.

Current Status and Trends of Research on Anthracycline-Induced Cardiotoxicity from 2002 to 2021: A Twenty-Year Bibliometric and Visualization Analysis

“…In addition, recent research indicated that the glutathione S-transferase [GST] μ 1 (GSTM1) appears to be an important gene in predisposition to ACT in survivors of childhood cancer [ 113 ]. To date, multiple genes and intergenic variants have now emerged as risk loci for ACT, including the solute carrier family 22 member 7 (SLC22A7), the ATP binding cassette subfamily C member 1 (ABCC1), the carbonyl reductase 3 (CBR3), the neutrophil cytosolic factor 4 (NCF4), and transient receptor potential cation channel subunit 6 (TRPC6) [ 114 , 115 ]. Recently, a gene regulatory network has been constructed and further screened several key ones among identified genes, including the ryanodine receptor 2 (RYR2), the tumor necrosis factor receptor superfamily member 12A (TNFRSF12A), and the sodium voltage-gated channel beta subunit 3 (SCN3B) [ 116 ].…”

Natural products and drug discovery

“…That entity contains a minimal version of the sugar daunosamine. All of these molecules have some cardiotoxicity and in general, treatment with these agents is limited to a number of treatment courses, often based upon the age of the patient [ 33 ].…”

Genetic Susceptibility and Mechanisms Underlying the Pathogenesis of Anthracycline-Associated Cardiotoxicity

“…Notably, combined effects of clinical risk factors and genetic variants would likely further increase the risk to develop AIC in patients who received anthracycline drug chemotherapy [ 44 , 45 ]. To date, mostly through human genetic studies of both pediatric and adult cancer survivors, variants in approximately 40 affected genes have been identified to be associated with the severity of AIC, with a small portion replicated in independent patient cohorts and/or functionally validated in animal models [ 4 , 5 , 21 , 22 ]. Below, we will discuss some key pharmacogenetic variants identified to either increase or reduce the risk of AIC based on the mechanisms of action on the affected genes according to literature reports.…”

“…Both approaches have yielded more than 60 significant single nucleotide polymorphisms (SNPs) in approximately 40 affected genes [ 4 , 5 , 21 ]. Notably, most of the human genetic studies aiming to identify variants associated with AIC reported in the literature are limited by relatively small sample sizes and a lack of independent replication and functional validation [ 4 , 5 , 22 , 23 ]. Here, in this brief review, we first discuss the well-studied and emerging mechanisms underlying the pathogenesis of AIC ( Figure 1 ).…”