Hematopoietic cell transplantation (HCT

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Haematopoietic cell transplantation (HCT) survivors are at increased risk for developing congestive heart failure (CHF), primarily due to pre-HCT exposure to anthracyclines. We examined the association between the development of CHF after HCT and polymorphisms in 16 candidate genes involved in anthracycline metabolism, iron homeostasis, anti-oxidant defence, and myocardial remodelling. A nested case-control study design was used. Cases (post-HCT CHF) were identified from 2,950 patients who underwent HCT between 1988 and 2007 at City of Hope and had survived ≥1 year. This cohort formed the sampling frame for selecting controls (without CHF) matched on: age, race/ethnicity, cumulative anthracycline exposure, stem cell source (allogeneic, autologous), and length of follow-up. Seventy-seven cases with pre-HCT germline DNA and 178 controls were genotyped. Multivariate analysis revealed that the odds of CHF was higher in females (Odds Ratio [OR]=2.9, p<0.01), individuals with pre-HCT chest radiation (OR=4.7, p=0.05), hypertension (OR=2.9, p=0.01), and with variants of genes coding for the NAD(P)H-oxidase subunit RAC2 (rs13058338, 7508T→A; OR=2.8, p<0.01), HFE (rs1799945, 63C→G; OR=2.5, p=0.05) or the doxorubicin efflux transporter ABCC2 (rs8187710, 1515G→A; OR=4.3, p<0.01). A combined (clinical and genetic) CHF predictive model performed better (area under the curve [AUC], 0.79) than the genetic (AUC=0.67) or the clinical (AUC=0.69) models alone.

Purpose To examine the utility and reliability of obtaining early echocardiographic measurements of left ventricular (LV) remodeling as well as blood biomarkers of cardiac injury in asymptomatic childhood cancer survivors at risk for LV dysfunction and congestive heart failure due to past exposure to anthracycline chemotherapy. Experimental Design Using a cross-sectional design, anthracycline-exposed childhood cancer survivors with preserved EF (≥50%) were evaluated using early echocardiographic indices and blood biomarkers of LV dysfunction. Survivors treated with ≥300mg/m2 anthracyclines (high-risk [HR]: n=100) were compared with: i) those treated with <300 mg/m2 anthracyclines (low-risk [LR]: n=50) and matched healthy controls (HC: n=50). All echocardiograms were interpreted by an institutional cardiologist and a study cardiologist blinded to risk status. Results Time from diagnosis was comparable for HR (12.0y) and LR (13.2y, p=0.8) survivors. Echocardiograms: HR had lower LV thickness-dimension ratio (Z-score: HR: −0.62, LR: −0.03, HC: −0.02; p<0.001), increased LV wall stress (HR: 66.7 g/cm2, LR: 56.6 g/cm2, HC: 54.2 g/cm2; p<0.01) and higher myocardial performance index (HR: 0.51, LR: 0.46, HC: 0.46; P<0.01). Inter-observer correlation (clinical/blinded reading) for all echocardiographic indices was excellent (range: R=0.76-0.97, p<0.001). Blood biomarkers: With the exception of NT-proBNP (r=0.28, p<0.01), there was no correlation between blood biomarkers (BNP, Troponin-T, ST-2, Galectin-3) and LV dysfunction. Conclusion Childhood cancer survivors with preserved EF 10+years from anthracycline exposure had dose-dependent changes in echocardiographic markers of LV dysfunction.

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