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

Abstract

589 Background: 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. Methods: 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). Results: 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). Conclusion: 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. Disclosures: No relevant conflicts of interest to declare.

Impact of hemochromatosis gene mutations on cardiac status in doxorubicin‐treated survivors of childhood high‐risk leukemia

“…4 Furthermore, the risk of anthracycline-related CHF may be modified by the presence of HFE variants, as shown in anthracycline-treated survivors of hematopoietic cell transplantation. 28 Cascales et al retrospectively evaluated cardiac iron, cardiac events, and HFE genotypes (C282Y and H63D) in 97 consecutive autopsy results from patients with solid and hematological cancers, 48 of whom had been treated with anthracyclines and 49 who received no chemotherapy (n 5 25) or nonanthracycline chemotherapy (n 5 24). 29 Patients treated with cumulative anthracycline doses > 200 mg/m 2 were found to have higher heart iron concentrations (490 lg/g dry weight vs 240 lg/g dry weight; P 5 .01), independently of liver iron load or transfusion history, compared with controls.…”

Cardiovascular disease in survivors of hematopoietic cell transplantation

“…Susceptibility due to inherited genetic variations in these pathways could explain the interindividual variability in the risk of anthracycline‐related CHF. Using a candidate gene approach, a recent study identified variants in genes involved in free radical generation ( RAC2 ), iron homeostasis (hemochromatosis gene [ HFE ]), and anthracycline metabolism (ATP‐binding cassette, sub‐family C [ ABCC2 ]) as independent predictors of post‐HCT CHF risk. In fact, a combined clinical (female sex, hypertension, and pre‐HCT chest radiotherapy exposure) and genetic ( RAC2 [rs13058338], 7508T→A; HFE [rs1799945], 63C→G; ABCC2 [rs8187710], and 1515G→A) CHF predictive model performed better (area under the curve [AUC], 0.79) than the genetic (AUC, 0.67) or clinical (AUC, 0.69) models alone, accurately predicting the likelihood of CHF in up to 80% of survivors of HCT in the study .…”

“…Using a candidate gene approach, a recent study identified variants in genes involved in free radical generation ( RAC2 ), iron homeostasis (hemochromatosis gene [ HFE ]), and anthracycline metabolism (ATP‐binding cassette, sub‐family C [ ABCC2 ]) as independent predictors of post‐HCT CHF risk. In fact, a combined clinical (female sex, hypertension, and pre‐HCT chest radiotherapy exposure) and genetic ( RAC2 [rs13058338], 7508T→A; HFE [rs1799945], 63C→G; ABCC2 [rs8187710], and 1515G→A) CHF predictive model performed better (area under the curve [AUC], 0.79) than the genetic (AUC, 0.67) or clinical (AUC, 0.69) models alone, accurately predicting the likelihood of CHF in up to 80% of survivors of HCT in the study . These data, when confirmed in an independent cohort, could form the basis for novel approaches for prevention in at‐risk survivors of HCT; these would include targeted screening (eg, patients of female sex, those with pre‐HCT chest radiotherapy exposure, those with the presence of an at‐risk genotype), behavior modification (eg, adoption of a healthy lifestyle, aggressive management of CVRFs such as hypertension), and early pharmacologic intervention (angiotensin‐converting enzyme [ACE] inhibitors or beta‐blockers) for high‐risk survivors with early evidence of cardiac dysfunction after HCT.…”