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.

Keywords: Adriamycin; CBR3; TRPC6; cardiomyopathy; cardiotoxicity; chemotherapy; doxorubicin; pharmacogenetics; risk variants.

Figure 1

Multiple putative risk genes and pathways of anthracycline-related cardiotoxicity. Putative risk genes are shown in uppercase italics within their proposed pathway of cardiotoxicity: (1) Calcium dysregulation; (2) Transport and metabolism; (3) Interaction with TOP2B; (4) Generation of Reactive Oxygen Species (ROS); (5) Iron homeostasis. Arrows mark pathways and potential interaction between pathways of cardiotoxicity. For example, generation of ROS and loss of iron homeostasis results in mitochondriopathy and cytosolic calcium overflow, but interaction of anthracycline with TOP2B also results in down-regulation of PGC1a and subsequent cytosolic calcium overflow. Increased TRPC6 expression or activity is influenced by genetic variants and results in increased calcium influx, but doxorubicin alone may also increase TRPC6 activity. Genetic variants in anthracycline transport and metabolism-related genes will affect the level of intracellular anthracyclines and their different metabolites and potentially increase (+) or decrease TRPC6 activation. ?, effect of metabolite or variant not known.