Genetic Susceptibility to Anthracycline-Related Congestive Heart Failure (CHF) in Survivors of Hematopoietic Cell Transplantation (HCT)

HCT survivors are at increased risk for developing cardiovascular disease, including CHF. We have demonstrated that the risk of post-HCT CHF is primarily ascribed to pre-HCT exposure to anthracyclines. The anthracycline-related cardiotoxicity is dose-dependent, with well-established factors that modify this association, such as young age at exposure to anthracyclines, female gender, chest irradiation, and presence of conventional cardiovascular risk factors (CVRFs: hypertension, diabetes mellitus, and dyslipidemia). However, these modifiers fail to explain the wide inter-individual variability in the risk of anthracycline-related CHF. Proposed pathogenesis of anthracycline-related CHF includes oxidative stress and intracardiac metabolic derangements induced by anthracycline toxic metabolites. Inherent susceptibility in these pathways could explain the inter-individual variability in risk – an area that is unstudied in this population.

A nested case-control approach was used to evaluate the impact of functional SNPs in candidate genes hypothesized to be associated with anthracycline-related CHF. Cases were defined per the American Heart Association criteria for clinical CHF. Individuals with CHF and with pre-HCT germline DNA were identified from 2950 patients transplanted at City of Hope between 1988 and 2007. This cohort formed the sampling frame for selecting controls (without CHF) matched on: age at HCT, type of HCT (allo, auto), race/ethnicity confirmed by genetic ancestry, anthracycline dose, and length of follow-up. We studied genes involved in free radical metabolism (NAD[P]H oxidase: subunits NCF4, RAC2, CYBA; Hemochromatosis: HFE; Superoxide dismutase: SOD; Apolipoprotein E: ApoE), genes involved in regulation of the renin-angiotensin and beta-adrenergic systems (AGT, AGTR1, ACE, ADRB1, ADRB2) as well as those impacting the pharmacodynamics of anthracyclines (carbonyl reductase: CBR1 and CBR3; Multidrug resistant protein: MRP1 and MRP2).

The cumulative incidence of CHF was 6% at 15 years after transplantation; Pre-HCT germline DNA was available for 77 patients with CHF; median age at HCT was 47.5 yrs (16.0–68.6); 82% underwent autologous HCT; 60% were non-Hispanic white; median anthracycline dose was 300 mg/m² (60–650); median time to CHF: 2.8 yrs (0.1–12.7). One-hundred and seventy eight matched controls with available germline DNA were identified. There was no difference in underlying diagnosis, conditioning regimen, and body mass index (BMI) at HCT between cases and controls. Cases were more likely to be female (55.8% vs. 34%, p<0.01), to have received chest radiation prior to HCT (14.3% vs. 5.1%, p=0.01), and have hypertension following HCT (28.6% vs. 14.6%, p<0.01) when compared to controls. Multivariate conditional logistic regression revealed an increased risk of CHF in individuals with variants of genes coding for the NAD(P)H oxidase subunit RAC2 (rs13058338, 7508T→A; Odds Ratio [OR]: 2.8, p<0.01), HFE (rs17999945, 63C→G; OR: 2.5, p=0.01) or the doxorubicin efflux transporter MRP2 (rs8187710, Cys1515Tyr; OR: 4.3, p<0.01). Compared to males with one or no at-risk alleles, female HCT survivors with ≥2 at-risk alleles were at highest risk of CHF (Table; OR=17.1, p<0.01).

Our findings support the “unifying hypothesis” that the risk of anthracycline-related cardiotoxicity is significantly modified by high-risk variants of RAC2 (free radical generation), HFE (dysregulation of iron homeostasis and free radical generation), and MRP2 (intracellular accumulation of cardiotoxic anthracyclines). These data could facilitate the development of novel approaches for targeted surveillance as well as early intervention strategies in HCT survivors at highest risk for CHF.

Model adjusted for: chest radiation exposure, BMI, underlying diagnosis, post-HCT CVRFs (hypertension, diabetes, dyslipidemia).

Case-Control matching criteria: age at HCT, race/ethnicity, lifetime anthracycline dose, type of HCT, length of follow-up.

No relevant conflicts of interest to declare.